diff --git a/Makefile b/Makefile
index 09199aa1c..a158a126a 100644
--- a/Makefile
+++ b/Makefile
@@ -231,7 +231,7 @@ bcftools_h = bcftools.h $(htslib_hts_defs_h) $(htslib_vcf_h) $(htslib_synced_bcf
 call_h = call.h $(htslib_vcf_h) $(htslib_synced_bcf_reader_h) vcmp.h
 variantkey_h = variantkey.h hex.h
 convert_h = convert.h $(htslib_vcf_h)
-tsv2vcf_h = tsv2vcf.h $(htslib_vcf_h)
+tsv2vcf_h = tsv2vcf.h $(htslib_vcf_h) $(bcftools_h)
 filter_h = filter.h $(htslib_vcf_h)
 gvcf_h = gvcf.h $(bcftools_h)
 khash_str2str_h = khash_str2str.h $(htslib_khash_h)
diff --git a/abuf.c b/abuf.c
index b125679b9..98f133f71 100644
--- a/abuf.c
+++ b/abuf.c
@@ -721,7 +721,7 @@ static inline int _is_acgtn(char *seq)
 {
     while ( *seq )
     {
-        char c = toupper(*seq);
+        char c = toupper_c(*seq);
         if ( c!='A' && c!='C' && c!='G' && c!='T' && c!='N' ) return 0;
         seq++;
     }
diff --git a/bam2bcf_indel.c b/bam2bcf_indel.c
index 975504f8a..b48509a24 100644
--- a/bam2bcf_indel.c
+++ b/bam2bcf_indel.c
@@ -36,6 +36,9 @@ DEALINGS IN THE SOFTWARE.  */
 #include <htslib/ksort.h>
 KSORT_INIT_GENERIC(uint32_t)
 
+// Avoid having to include all of bcftools.h
+static inline char toupper_c(char c) { return toupper((unsigned char) c); }
+
 #define MINUS_CONST 0x10000000
 
 #define MAX_TYPES 64
@@ -89,8 +92,8 @@ inline int est_indelreg(int pos, const char *ref, int l, char *ins4)
     int i, j, max = 0, max_i = pos, score = 0;
     l = abs(l);
     for (i = pos + 1, j = 0; ref[i]; ++i, ++j) {
-        if (ins4) score += (toupper(ref[i]) != "ACGTN"[(int)ins4[j%l]])? -10 : 1;
-        else score += (toupper(ref[i]) != toupper(ref[pos+1+j%l]))? -10 : 1;
+        if (ins4) score += (toupper_c(ref[i]) != "ACGTN"[(int)ins4[j%l]])? -10 : 1;
+        else score += (toupper_c(ref[i]) != toupper_c(ref[pos+1+j%l]))? -10 : 1;
         if (score < 0) break;
         if (max < score) max = score, max_i = i;
     }
diff --git a/bam_sample.c b/bam_sample.c
index d8c10b8b3..aa1499868 100644
--- a/bam_sample.c
+++ b/bam_sample.c
@@ -295,18 +295,18 @@ int bam_smpl_add_samples(bam_smpl_t *bsmpl, char *list, int is_file)
         while ( *ptr )
         {
             if ( *ptr=='\\' && !escaped ) { escaped = 1; ptr++; continue; }
-            if ( isspace(*ptr) && !escaped ) break;
+            if ( isspace_c(*ptr) && !escaped ) break;
             kputc(*ptr, &ori);
             escaped = 0;
             ptr++;
         }
         if ( *ptr )
         {
-            while ( *ptr && isspace(*ptr) ) ptr++;
+            while ( *ptr && isspace_c(*ptr) ) ptr++;
             while ( *ptr )
             {
                 if ( *ptr=='\\' && !escaped ) { escaped = 1; ptr++; continue; }
-                if ( isspace(*ptr) && !escaped ) break;
+                if ( isspace_c(*ptr) && !escaped ) break;
                 kputc(*ptr, &ren);
                 escaped = 0;
                 ptr++;
@@ -343,18 +343,18 @@ int bam_smpl_add_readgroups(bam_smpl_t *bsmpl, char *list, int is_file)
         while ( *ptr )
         {
             if ( *ptr=='\\' && !escaped ) { escaped = 1; ptr++; continue; }
-            if ( isspace(*ptr) && !escaped ) break;
+            if ( isspace_c(*ptr) && !escaped ) break;
             kputc(*ptr, &fld1);
             escaped = 0;
             ptr++;
         }
         if ( *ptr )
         {
-            while ( *ptr && isspace(*ptr) ) ptr++;
+            while ( *ptr && isspace_c(*ptr) ) ptr++;
             while ( *ptr )
             {
                 if ( *ptr=='\\' && !escaped ) { escaped = 1; ptr++; continue; }
-                if ( isspace(*ptr) && !escaped ) break;
+                if ( isspace_c(*ptr) && !escaped ) break;
                 kputc(*ptr, &fld2);
                 escaped = 0;
                 ptr++;
@@ -362,11 +362,11 @@ int bam_smpl_add_readgroups(bam_smpl_t *bsmpl, char *list, int is_file)
         }
         if ( *ptr )
         {
-            while ( *ptr && isspace(*ptr) ) ptr++;
+            while ( *ptr && isspace_c(*ptr) ) ptr++;
             while ( *ptr )
             {
                 if ( *ptr=='\\' && !escaped ) { escaped = 1; ptr++; continue; }
-                if ( isspace(*ptr) && !escaped ) break;
+                if ( isspace_c(*ptr) && !escaped ) break;
                 kputc(*ptr, &fld3);
                 escaped = 0;
                 ptr++;
diff --git a/bcftools.h b/bcftools.h
index 5a4071d96..a06ce60d0 100644
--- a/bcftools.h
+++ b/bcftools.h
@@ -31,6 +31,7 @@ THE SOFTWARE.  */
 #include <htslib/synced_bcf_reader.h>
 #include <htslib/kfunc.h>
 #include <math.h>
+#include <ctype.h>
 
 #define FT_TAB_TEXT 0       // custom tab-delimited text file
 #define FT_GZ 1
@@ -184,4 +185,20 @@ static inline int get_unseen_allele(bcf1_t *line)
     return 0;
 }
 
+// <ctype.h> wrappers, borrowed from htslib's textutils_internal.h
+// The <ctype.h> functions operate on ints such as are returned by fgetc(),
+// i.e., characters represented as unsigned-char-valued ints, or EOF.
+// To operate on plain chars (and to avoid warnings on some platforms),
+// technically one must cast to unsigned char everywhere (see CERT STR37-C)
+// or less painfully use these *_c() functions that operate on plain chars
+// (but not EOF, which must be considered separately where it is applicable).
+static inline int isalnum_c(char c) { return isalnum((unsigned char) c); }
+static inline int isalpha_c(char c) { return isalpha((unsigned char) c); }
+static inline int isdigit_c(char c) { return isdigit((unsigned char) c); }
+static inline int isprint_c(char c) { return isprint((unsigned char) c); }
+static inline int ispunct_c(char c) { return ispunct((unsigned char) c); }
+static inline int isspace_c(char c) { return isspace((unsigned char) c); }
+static inline char tolower_c(char c) { return tolower((unsigned char) c); }
+static inline char toupper_c(char c) { return toupper((unsigned char) c); }
+
 #endif
diff --git a/consensus.c b/consensus.c
index 166a4de16..c95753c27 100644
--- a/consensus.c
+++ b/consensus.c
@@ -339,7 +339,7 @@ static void destroy_data(args_t *args)
 static void init_region(args_t *args, char *line)
 {
     char *ss, *se = line;
-    while ( *se && !isspace(*se) && *se!=':' ) se++;
+    while ( *se && !isspace_c(*se) && *se!=':' ) se++;
     hts_pos_t from = 0, to = 0;
     char tmp = 0, *tmp_ptr = NULL;
     if ( *se )
@@ -353,7 +353,7 @@ static void init_region(args_t *args, char *line)
             from--;
             ss = ++se;
             to = strtol(ss,&se,10);
-            if ( ss==se || (*se && !isspace(*se)) ) { from = 0; to = 0; }
+            if ( ss==se || (*se && !isspace_c(*se)) ) { from = 0; to = 0; }
             else to--;
         }
     }
@@ -500,9 +500,9 @@ static void mark_ins(char *ref, char *alt, char mark)
 {
     int i, nref = strlen(ref), nalt = strlen(alt);
     if ( mark==TO_LOWER )
-        for (i=nref; i<nalt; i++) alt[i] = tolower(alt[i]);
+        for (i=nref; i<nalt; i++) alt[i] = tolower_c(alt[i]);
     else if ( mark==TO_UPPER )
-        for (i=nref; i<nalt; i++) alt[i] = toupper(alt[i]);
+        for (i=nref; i<nalt; i++) alt[i] = toupper_c(alt[i]);
     else if ( mark )
         for (i=nref; i<nalt; i++) alt[i] = mark;
 }
@@ -513,22 +513,17 @@ static void mark_snv(char *ref, char *alt, char mark)
     if ( mark==TO_LOWER )
     {
         for (i=0; i<n; i++)
-            if ( tolower(ref[i])!=tolower(alt[i]) ) alt[i] = tolower(alt[i]);
+            if ( tolower_c(ref[i])!=tolower_c(alt[i]) ) alt[i] = tolower_c(alt[i]);
     }
     else if ( mark==TO_UPPER)
     {
         for (i=0; i<n; i++)
-            if ( tolower(ref[i])!=tolower(alt[i]) ) alt[i] = toupper(alt[i]);
-    }
-    else if ( mark==TO_UPPER)
-    {
-        for (i=0; i<n; i++)
-            if ( tolower(ref[i])!=tolower(alt[i]) ) alt[i] = toupper(alt[i]);
+            if ( tolower_c(ref[i])!=tolower_c(alt[i]) ) alt[i] = toupper_c(alt[i]);
     }
     else if ( mark )
     {
         for (i=0; i<n; i++)
-            if ( tolower(ref[i])!=tolower(alt[i]) ) alt[i] = mark;
+            if ( tolower_c(ref[i])!=tolower_c(alt[i]) ) alt[i] = mark;
     }
 }
 static void iupac_init(args_t *args, bcf1_t *rec)
@@ -943,7 +938,7 @@ static void apply_variant(args_t *args, bcf1_t *rec)
         // one base overlap
 
         int fail = 1;
-        if ( args->prev_base_pos==rec->pos && toupper(ref_allele[0])==toupper(args->prev_base) )
+        if ( args->prev_base_pos==rec->pos && toupper_c(ref_allele[0])==toupper_c(args->prev_base) )
         {
             if ( rec->rlen==1 ) fail = 0;
             else if ( !strncasecmp(ref_allele+1,args->fa_buf.s+idx+1,rec->rlen-1) ) fail = 0;
@@ -992,11 +987,11 @@ static void apply_variant(args_t *args, bcf1_t *rec)
     }
 
     int safe_idx = idx<0 ? 0 : idx; // idx can be negative in case of overlapping deletion
-    args->fa_case = toupper(args->fa_buf.s[safe_idx])==args->fa_buf.s[safe_idx] ? TO_UPPER : TO_LOWER;
+    args->fa_case = toupper_c(args->fa_buf.s[safe_idx])==args->fa_buf.s[safe_idx] ? TO_UPPER : TO_LOWER;
     if ( args->fa_case==TO_UPPER )
-        for (i=0; i<alen; i++) alt_allele[i] = toupper(alt_allele[i]);
+        for (i=0; i<alen; i++) alt_allele[i] = toupper_c(alt_allele[i]);
     else
-        for (i=0; i<alen; i++) alt_allele[i] = tolower(alt_allele[i]);
+        for (i=0; i<alen; i++) alt_allele[i] = tolower_c(alt_allele[i]);
 
     if ( args->mark_ins && len_diff>0 )
         mark_ins(ref_allele, alt_allele, args->mark_ins);
@@ -1080,9 +1075,9 @@ static void mask_region(args_t *args, char *seq, int len)
             if ( idx_start < 0 ) idx_start = 0;
             if ( idx_end >= len ) idx_end = len - 1;
             if ( mask->with==MASK_UC )
-                for (j=idx_start; j<=idx_end; j++) seq[j] = toupper(seq[j]);
+                for (j=idx_start; j<=idx_end; j++) seq[j] = toupper_c(seq[j]);
             else if ( mask->with==MASK_LC )
-                for (j=idx_start; j<=idx_end; j++) seq[j] = tolower(seq[j]);
+                for (j=idx_start; j<=idx_end; j++) seq[j] = tolower_c(seq[j]);
             else
                 for (j=idx_start; j<=idx_end; j++) seq[j] = mask->with;
         }
@@ -1124,7 +1119,7 @@ static void consensus(args_t *args)
         args->fa_src_pos += str.l;
 
         // determine if uppercase or lowercase is used in this fasta file
-        if ( args->fa_case==-1 ) args->fa_case = toupper(str.s[0])==str.s[0] ? 1 : 0;
+        if ( args->fa_case==-1 ) args->fa_case = toupper_c(str.s[0])==str.s[0] ? 1 : 0;
 
         if ( args->mask ) mask_region(args, str.s, str.l);
         kputs(str.s, &args->fa_buf);
diff --git a/convert.c b/convert.c
index 43cdf507e..ad5bc4043 100644
--- a/convert.c
+++ b/convert.c
@@ -1461,7 +1461,7 @@ static int parse_subscript(char **p)
     char *q = *p;
     if ( *q!='{' ) return -1;
     q++;
-    while ( *q && *q!='}' && isdigit(*q) ) q++;
+    while ( *q && *q!='}' && isdigit_c(*q) ) q++;
     if ( *q!='}' ) return -1;
     int idx = atoi((*p)+1);
     *p = q+1;
@@ -1474,7 +1474,7 @@ static char *parse_tag(convert_t *convert, char *p, int is_gtf)
     if ( is_vcf_column ) p++;
 
     char *q = ++p;
-    while ( *q && (isalnum(*q) || *q=='_' || *q=='.') ) q++;
+    while ( *q && (isalnum_c(*q) || *q=='_' || *q=='.') ) q++;
     kstring_t str = {0,0,0};
     if ( q-p==0 ) error("Could not parse format string: %s\n", convert->format_str);
     kputsn(p, q-p, &str);
@@ -1517,7 +1517,7 @@ static char *parse_tag(convert_t *convert, char *p, int is_gtf)
             }
             p = ++q;
             str.l = 0;
-            while ( *q && (isalnum(*q) || *q=='_' || *q=='.') ) q++;
+            while ( *q && (isalnum_c(*q) || *q=='_' || *q=='.') ) q++;
             if ( q-p==0 ) error("Could not parse format string: %s\n", convert->format_str);
             kputsn(p, q-p, &str);
             fmt_t *fmt = register_tag(convert, str.s, is_gtf, T_INFO);
@@ -1567,7 +1567,7 @@ static char *parse_tag(convert_t *convert, char *p, int is_gtf)
             {
                 p = ++q;
                 str.l = 0;
-                while ( *q && (isalnum(*q) || *q=='_' || *q=='.') ) q++;
+                while ( *q && (isalnum_c(*q) || *q=='_' || *q=='.') ) q++;
                 if ( q-p==0 ) error("Could not parse format string: %s\n", convert->format_str);
                 kputsn(p, q-p, &str);
                 fmt_t *fmt = register_tag(convert, str.s, is_gtf, T_INFO);
diff --git a/csq.c b/csq.c
index 9572fd32b..3007ef3d1 100644
--- a/csq.c
+++ b/csq.c
@@ -2844,7 +2844,7 @@ static int sanity_check_ref(args_t *args, gf_tscript_t *tr, bcf1_t *rec)
     int i = 0;
     while ( ref[i] && vcf[i] )
     {
-        if ( ref[i]!=vcf[i] && toupper(ref[i])!=toupper(vcf[i]) )
+        if ( ref[i]!=vcf[i] && toupper_c(ref[i])!=toupper_c(vcf[i]) )
         {
             if ( !args->force )
                 error("Error: the fasta reference does not match the VCF REF allele at %s:%"PRId64" .. fasta=%c vcf=%c\n",
diff --git a/filter.c b/filter.c
index 75d74b77b..686bace32 100644
--- a/filter.c
+++ b/filter.c
@@ -183,15 +183,15 @@ inline static void tok_init_samples(token_t *atok, token_t *btok, token_t *rtok)
 static int filters_next_token(char **str, int *len)
 {
     char *tmp = *str;
-    while ( *tmp && isspace(*tmp) ) tmp++;
+    while ( *tmp && isspace_c(*tmp) ) tmp++;
     *str = tmp;
     *len = 0;
 
     // test for doubles: d.ddde[+-]dd
-    if ( isdigit(*str[0]) || *str[0]=='.' )   // strtod would eat +/-
+    if ( isdigit_c(*str[0]) || *str[0]=='.' )   // strtod would eat +/-
     {
         double HTS_UNUSED v = strtod(*str, &tmp);
-        if ( *str!=tmp && (!tmp[0] || !isalnum(tmp[0])) )
+        if ( *str!=tmp && (!tmp[0] || !isalnum_c(tmp[0])) )
         {
             *len = tmp - (*str);
             return TOK_VAL;
@@ -246,7 +246,7 @@ static int filters_next_token(char **str, int *len)
 
     if ( tmp[0]=='@' )  // file name
     {
-        while ( *tmp && !isspace(*tmp) && *tmp!='=' && *tmp!='!' ) tmp++;
+        while ( *tmp && !isspace_c(*tmp) && *tmp!='=' && *tmp!='!' ) tmp++;
         *len = tmp - (*str);
         return TOK_VAL;
     }
@@ -258,7 +258,7 @@ static int filters_next_token(char **str, int *len)
         {
             if ( tmp[0]=='"' ) break;
             if ( tmp[0]=='\'' ) break;
-            if ( isspace(tmp[0]) ) break;
+            if ( isspace_c(tmp[0]) ) break;
             if ( tmp[0]=='<' ) break;
             if ( tmp[0]=='>' ) break;
             if ( tmp[0]=='=' ) break;
@@ -3202,7 +3202,7 @@ static int filters_init1(filter_t *filter, char *str, int len, token_t *tok)
         for (i=0; i<n; i++)
         {
             char *se = list[i];
-            while ( *se && !isspace(*se) ) se++;
+            while ( *se && !isspace_c(*se) ) se++;
             *se = 0;
             if ( !khash_str2int_has_key(tok->hash,list[i]) )
                 khash_str2int_inc(tok->hash,list[i]);
@@ -3541,7 +3541,7 @@ static void filter_debug_print(token_t *toks, token_t **tok_ptrs, int ntoks)
 
 static void str_to_lower(char *str)
 {
-    while ( *str ) { *str = tolower(*str); str++; }
+    while ( *str ) { *str = tolower_c(*str); str++; }
 }
 static int perl_exec(filter_t *flt, bcf1_t *line, token_t *rtok, token_t **stack, int nstack)
 {
@@ -3606,7 +3606,7 @@ static int perl_exec(filter_t *flt, bcf1_t *line, token_t *rtok, token_t **stack
 static void perl_init(filter_t *filter, char **str)
 {
     char *beg = *str;
-    while ( *beg && isspace(*beg) ) beg++;
+    while ( *beg && isspace_c(*beg) ) beg++;
     if ( !*beg ) return;
     if ( strncasecmp("perl:", beg, 5) ) return;
 #if ENABLE_PERL_FILTERS
@@ -3840,7 +3840,7 @@ static filter_t *filter_init_(bcf_hdr_t *hdr, const char *str, int exit_on_error
 
                 if ( ret == TOK_PERLSUB )
                 {
-                    while ( *beg && ((isalnum(*beg) && !ispunct(*beg)) || *beg=='_') ) beg++;
+                    while ( *beg && ((isalnum_c(*beg) && !ispunct_c(*beg)) || *beg=='_') ) beg++;
                     if ( *beg!='(' ) error("[%s:%d] Could not parse the expression: %s\n", __FILE__,__LINE__,str);
 
                     // the subroutine name
@@ -3900,7 +3900,7 @@ static filter_t *filter_init_(bcf_hdr_t *hdr, const char *str, int exit_on_error
         }
         else if ( !len )    // all tokes read or an error
         {
-            if ( *tmp && !isspace(*tmp) ) error("Could not parse the expression: [%s]\n", str);
+            if ( *tmp && !isspace_c(*tmp) ) error("Could not parse the expression: [%s]\n", str);
             break;     // all tokens read
         }
         else           // TOK_VAL: annotation name or value
diff --git a/mcall.c b/mcall.c
index 13383787e..ced4f53de 100644
--- a/mcall.c
+++ b/mcall.c
@@ -31,6 +31,9 @@ THE SOFTWARE.  */
 #include "call.h"
 #include "prob1.h"
 
+// Avoid having to include all of bcftools.h
+static inline int isspace_c(char c) { return isspace((unsigned char) c); }
+
 // Using priors for GTs does not seem to be mathematically justified. Although
 // it seems effective in removing false calls, it also flips a significant
 // proportion of HET genotypes. Better is to filter by FORMAT/GQ using
@@ -308,10 +311,10 @@ static void init_sample_groups(call_t *call)
         for (i=0; i<nlines; i++)
         {
             char *ptr = lines[i];
-            while ( *ptr && !isspace(*ptr) ) ptr++;
+            while ( *ptr && !isspace_c(*ptr) ) ptr++;
             if ( !*ptr ) error("Could not parse the line in %s, expected a sample name followed by tab and a population name: %s\n",call->sample_groups,lines[i]);
             char *tmp = ptr;
-            while ( *ptr && isspace(*ptr) ) ptr++;
+            while ( *ptr && isspace_c(*ptr) ) ptr++;
             if ( !*ptr ) error("Could not parse the line in %s, expected a sample name followed by tab and a population name: %s\n",call->sample_groups,lines[i]);
             *tmp = 0;
             int ismpl = bcf_hdr_id2int(call->hdr, BCF_DT_SAMPLE, lines[i]);
diff --git a/mpileup.c b/mpileup.c
index 00d21dbe5..8afd9edd9 100644
--- a/mpileup.c
+++ b/mpileup.c
@@ -1074,7 +1074,7 @@ int read_file_list(const char *file_list,int *n,char **argv[])
     {
         // allow empty lines and trailing spaces
         len = strlen(buf);
-        while ( len>0 && isspace(buf[len-1]) ) len--;
+        while ( len>0 && isspace_c(buf[len-1]) ) len--;
         if ( !len ) continue;
 
         // check sanity of the file list
@@ -1084,7 +1084,7 @@ int read_file_list(const char *file_list,int *n,char **argv[])
             // no such file, check if it is safe to print its name
             int i, safe_to_print = 1;
             for (i=0; i<len; i++)
-                if (!isprint(buf[i])) { safe_to_print = 0; break; }
+                if (!isprint_c(buf[i])) { safe_to_print = 0; break; }
             if ( safe_to_print )
                 fprintf(stderr,"The file list \"%s\" appears broken, could not locate: %s\n", file_list,buf);
             else
diff --git a/mpileup2/mpileup.c b/mpileup2/mpileup.c
index 86ccf6145..fdb9803f8 100644
--- a/mpileup2/mpileup.c
+++ b/mpileup2/mpileup.c
@@ -492,7 +492,7 @@ static int mplp_add_bam(mpileup_t *mplp, char *bam, int is_file)
                 char *tmp = names[i];
                 while ( *tmp )
                 {
-                    if ( !isprint(*tmp) ) break;
+                    if ( !isprint((unsigned char) *tmp) ) break;
                     tmp++;
                 }
                 if ( !*tmp )
diff --git a/ploidy.c b/ploidy.c
index d0884dcc4..965bda103 100644
--- a/ploidy.c
+++ b/ploidy.c
@@ -62,8 +62,8 @@ int ploidy_parse(const char *line, char **chr_beg, char **chr_end, uint32_t *beg
     int default_ploidy_def = 0;
 
     char *ss = (char*) line;
-    while ( *ss && isspace(*ss) ) ss++;
-    if ( ss[0]=='*' && (!ss[1] || isspace(ss[1])) )
+    while ( *ss && isspace_c(*ss) ) ss++;
+    if ( ss[0]=='*' && (!ss[1] || isspace_c(ss[1])) )
         default_ploidy_def = 1; // definition of default ploidy, chr="*"
     else
     {
@@ -74,18 +74,18 @@ int ploidy_parse(const char *line, char **chr_beg, char **chr_end, uint32_t *beg
 
     // Skip the fields already parsed by regidx_parse_tab
     ss = (char*) line;
-    while ( *ss && isspace(*ss) ) ss++;
+    while ( *ss && isspace_c(*ss) ) ss++;
     for (i=0; i<3; i++)
     {
-        while ( *ss && !isspace(*ss) ) ss++;
+        while ( *ss && !isspace_c(*ss) ) ss++;
         if ( !*ss ) return -2;  // wrong number of fields
-        while ( *ss && isspace(*ss) ) ss++;
+        while ( *ss && isspace_c(*ss) ) ss++;
     }
     if ( !*ss ) return -2;
 
     // Parse the payload
     char *se = ss;
-    while ( *se && !isspace(*se) ) se++;
+    while ( *se && !isspace_c(*se) ) se++;
     if ( !*se || se==ss ) error("Could not parse: %s\n", line);
     ploidy->tmp_str.l = 0;
     kputsn(ss,se-ss,&ploidy->tmp_str);
@@ -102,7 +102,7 @@ int ploidy_parse(const char *line, char **chr_beg, char **chr_end, uint32_t *beg
     }
 
     ss = se;
-    while ( *se && isspace(*se) ) se++;
+    while ( *se && isspace_c(*se) ) se++;
     if ( !*se ) error("Could not parse: %s\n", line);
     sp->ploidy = strtol(ss,&se,10);
     if ( ss==se ) error("Could not parse: %s\n", line);
@@ -163,13 +163,13 @@ ploidy_t *ploidy_init_string(const char *str, int dflt)
     const char *ss = str;
     while ( *ss )
     {
-        while ( *ss && isspace(*ss) ) ss++;
+        while ( *ss && isspace_c(*ss) ) ss++;
         const char *se = ss;
         while ( *se && *se!='\r' && *se!='\n' ) se++;
         tmp.l = 0;
         kputsn(ss, se-ss, &tmp);
         regidx_insert(pld->idx,tmp.s);
-        while ( *se && isspace(*se) ) se++;
+        while ( *se && isspace_c(*se) ) se++;
         ss = se;
     }
     free(tmp.s);
diff --git a/plugins/fill-tags.c b/plugins/fill-tags.c
index 473bc1580..c803e617c 100644
--- a/plugins/fill-tags.c
+++ b/plugins/fill-tags.c
@@ -171,14 +171,14 @@ void parse_samples(args_t *args, char *fname)
         // NA12400 GRP1
         // NA18507 GRP1,GRP2
         char *pop_names = str.s + str.l - 1;
-        while ( pop_names >= str.s && isspace(*pop_names) ) pop_names--;
+        while ( pop_names >= str.s && isspace_c(*pop_names) ) pop_names--;
         if ( pop_names <= str.s ) error("Could not parse the file: %s\n", str.s);
         pop_names[1] = 0;   // trailing spaces
-        while ( pop_names >= str.s && !isspace(*pop_names) ) pop_names--;
+        while ( pop_names >= str.s && !isspace_c(*pop_names) ) pop_names--;
         if ( pop_names <= str.s ) error("Could not parse the file: %s\n", str.s);
 
         char *smpl = pop_names++;
-        while ( smpl >= str.s && isspace(*smpl) ) smpl--;
+        while ( smpl >= str.s && isspace_c(*smpl) ) smpl--;
         if ( smpl <= str.s+1 ) error("Could not parse the file: %s\n", str.s);
         smpl[1] = 0;
         smpl = str.s;
diff --git a/plugins/fixploidy.c b/plugins/fixploidy.c
index a6bc7757e..2cb6afbd1 100644
--- a/plugins/fixploidy.c
+++ b/plugins/fixploidy.c
@@ -87,11 +87,11 @@ void set_samples(char *fname, bcf_hdr_t *hdr, ploidy_t *ploidy, int *sample2sex)
     while ( hts_getline(fp, KS_SEP_LINE, &tmp) > 0 )
     {
         char *ss = tmp.s;
-        while ( *ss && isspace(*ss) ) ss++;
+        while ( *ss && isspace_c(*ss) ) ss++;
         if ( !*ss ) error("Could not parse: %s\n", tmp.s);
         if ( *ss=='#' ) continue;
         char *se = ss;
-        while ( *se && !isspace(*se) ) se++;
+        while ( *se && !isspace_c(*se) ) se++;
         char x = *se; *se = 0;
 
         int ismpl = bcf_hdr_id2int(hdr, BCF_DT_SAMPLE, ss);
@@ -99,10 +99,10 @@ void set_samples(char *fname, bcf_hdr_t *hdr, ploidy_t *ploidy, int *sample2sex)
 
         *se = x;
         ss = se+1;
-        while ( *ss && isspace(*ss) ) ss++;
+        while ( *ss && isspace_c(*ss) ) ss++;
         if ( !*ss )  error("Could not parse: %s\n", tmp.s);
         se = ss;
-        while ( *se && !isspace(*se) ) se++;
+        while ( *se && !isspace_c(*se) ) se++;
         if ( se==ss ) error("Could not parse: %s\n", tmp.s);
 
         sample2sex[ismpl] = ploidy_add_sex(ploidy, ss);
diff --git a/plugins/fixref.c b/plugins/fixref.c
index abb3367ea..b38ebbf12 100644
--- a/plugins/fixref.c
+++ b/plugins/fixref.c
@@ -278,7 +278,7 @@ static bcf1_t *set_ref_alt(args_t *args, bcf1_t *rec, const char ref, const char
 
 static inline int nt2int(char nt)
 {
-    nt = toupper(nt);
+    nt = toupper_c(nt);
     if ( nt=='A' ) return 0;
     if ( nt=='C' ) return 1;
     if ( nt=='G' ) return 2;
diff --git a/plugins/gvcfz.c b/plugins/gvcfz.c
index 91d43f159..4fcc24e21 100644
--- a/plugins/gvcfz.c
+++ b/plugins/gvcfz.c
@@ -130,7 +130,7 @@ static void init_groups(args_t *args)
     char *rmme_str = strdup(args->group_by), *beg = rmme_str;
     while ( *beg )
     {
-        while ( *beg && isspace(*beg) ) beg++;
+        while ( *beg && isspace_c(*beg) ) beg++;
         if ( !beg ) break;
         char *end = beg;
         while ( *end && *end!=':' ) end++;
@@ -155,8 +155,8 @@ static void init_groups(args_t *args)
         if ( !strcmp(flt,"PASS") ) grp->flt_id = -1;
 
         // remove trailing spaces
-        beg = grp->expr + strlen(grp->expr); while ( beg >= grp->expr && isspace(*beg) ) { *beg = 0; beg--; }
-        beg = grp->expr; while ( *beg && isspace(*beg) ) beg++;
+        beg = grp->expr + strlen(grp->expr); while ( beg >= grp->expr && isspace_c(*beg) ) { *beg = 0; beg--; }
+        beg = grp->expr; while ( *beg && isspace_c(*beg) ) beg++;
 
         grp->flt = strcmp("-",beg) ? filter_init(args->hdr_in, grp->expr) : NULL;
 
diff --git a/plugins/mendelian2.c b/plugins/mendelian2.c
index 837b97da2..0347cd0e2 100644
--- a/plugins/mendelian2.c
+++ b/plugins/mendelian2.c
@@ -235,12 +235,12 @@ static int parse_rules(const char *line, char **chr_beg, char **chr_end, uint32_
 
     // eat any leading spaces
     char *ss = (char*) line;
-    while ( *ss && isspace(*ss) ) ss++;
+    while ( *ss && isspace_c(*ss) ) ss++;
     if ( !*ss ) return -1;      // skip empty lines
 
     // sex id, e.g. 1X or 2X
     char keep, *tmp, *se = ss;
-    while ( *se && !isspace(*se) ) se++;
+    while ( *se && !isspace_c(*se) ) se++;
     if ( !*se ) error("Could not parse the sex ID in the region line: %s\n", line);
     keep = *se;
     *se = 0;
@@ -252,13 +252,13 @@ static int parse_rules(const char *line, char **chr_beg, char **chr_end, uint32_
         sex_id = args->nsex_id++;
     }
     *se = keep;
-    while ( *se && isdigit(*se) ) se++;
-    while ( *se && isspace(*se) ) se++;
+    while ( *se && isdigit_c(*se) ) se++;
+    while ( *se && isspace_c(*se) ) se++;
     ss = se;
 
     // chromosome name, beg, end
-    while ( se[1] && !isspace(se[1]) ) se++;
-    while ( se > ss && isdigit(*se) ) se--;
+    while ( se[1] && !isspace_c(se[1]) ) se++;
+    while ( se > ss && isdigit_c(*se) ) se--;
     if ( *se!='-' ) error("Could not parse the region: %s\n",line);
     *end = strtol(se+1, &tmp, 10) - 1;
     if ( tmp==se+1 ) error("Could not parse the region: %s\n",line);
@@ -270,8 +270,8 @@ static int parse_rules(const char *line, char **chr_beg, char **chr_end, uint32_
     *chr_end = se-1;
 
     // skip region
-    while ( *ss && !isspace(*ss) ) ss++;
-    while ( *ss && isspace(*ss) ) ss++;
+    while ( *ss && !isspace_c(*ss) ) ss++;
+    while ( *ss && isspace_c(*ss) ) ss++;
 
     rule_t *rule = (rule_t*) payload;
     rule->sex_id = sex_id;
@@ -279,7 +279,7 @@ static int parse_rules(const char *line, char **chr_beg, char **chr_end, uint32_
     rule->ploidy   = 0;
 
     // alleles inherited from mother (M), father (F), both (MF), none (.)
-    while ( *ss && !isspace(*ss) )
+    while ( *ss && !isspace_c(*ss) )
     {
         if ( *ss=='M' ) { rule->inherits |= 1<<iMOM; rule->ploidy++; }
         else if ( *ss=='F' ) { rule->inherits |= 1<<iDAD; rule->ploidy++; }
diff --git a/plugins/scatter.c b/plugins/scatter.c
index ec68e56c9..2afd0e04c 100644
--- a/plugins/scatter.c
+++ b/plugins/scatter.c
@@ -117,12 +117,12 @@ void mkdir_p(const char *fmt, ...) HTS_FORMAT(HTS_PRINTF_FMT, 1, 2);
 int regidx_parse_reg_name(const char *line, char **chr_beg, char **chr_end, uint32_t *beg, uint32_t *end, void *payload, void *usr)
 {
     char *ss = (char*) line;
-    while ( *ss && isspace(*ss) ) ss++;
+    while ( *ss && isspace_c(*ss) ) ss++;
     if ( !*ss ) return -1;      // skip blank lines
     if ( *ss=='#' ) return -1;  // skip comments
 
     char *se = ss;
-    while ( *se && *se!=':' && !isspace(*se) ) se++;
+    while ( *se && *se!=':' && !isspace_c(*se) ) se++;
 
     *chr_beg = ss;
     *chr_end = se-1;
@@ -140,9 +140,9 @@ int regidx_parse_reg_name(const char *line, char **chr_beg, char **chr_end, uint
         if ( *beg==0 ) { fprintf(stderr,"Could not parse reg line, expected 1-based coordinate: %s\n", line); return -2; }
         (*beg)--;
 
-        if ( !se[0] || isspace(se[0])) {
+        if ( !se[0] || isspace_c(se[0])) {
             *end = *beg;
-        } else if ( se[0] == '-' && (!se[1] || isspace(se[1])) ) {
+        } else if ( se[0] == '-' && (!se[1] || isspace_c(se[1])) ) {
            *end = MAX_COOR_0;
            se++;
         } else {
@@ -155,7 +155,7 @@ int regidx_parse_reg_name(const char *line, char **chr_beg, char **chr_end, uint
     }
 
     ss = se;
-    while ( *ss && isspace(*ss) ) ss++;
+    while ( *ss && isspace_c(*ss) ) ss++;
     if ( !ss[0] ) ss = (char *)line;
 
     int *idx = (int *)payload;
@@ -180,7 +180,7 @@ static void open_set(subset_t *set, args_t *args)
     int k, l = args->str.l;
     if (args->prefix) kputs(args->prefix, &args->str);
     kputs(set->fname, &args->str);
-    for (k=l; k<args->str.l; k++) if ( isspace(args->str.s[k]) ) args->str.s[k] = '_';
+    for (k=l; k<args->str.l; k++) if ( isspace_c(args->str.s[k]) ) args->str.s[k] = '_';
     if ( args->output_type & FT_BCF ) kputs(".bcf", &args->str);
     else if ( args->output_type & FT_GZ ) kputs(".vcf.gz", &args->str);
     else kputs(".vcf", &args->str);
diff --git a/plugins/setGT.c b/plugins/setGT.c
index 6495006c3..7340f7f74 100644
--- a/plugins/setGT.c
+++ b/plugins/setGT.c
@@ -162,12 +162,12 @@ void parse_binom_expr(args_t *args, char *str)
     if ( str[1]!=':' ) _parse_binom_expr_error(str);
 
     char *beg = str+2;
-    while ( *beg && isspace(*beg) ) beg++;
+    while ( *beg && isspace_c(*beg) ) beg++;
     if ( !*beg ) _parse_binom_expr_error(str);
     char *end = beg;
     while ( *end )
     {
-        if ( isspace(*end) || *end=='<' || *end=='=' || *end=='>' ) break;
+        if ( isspace_c(*end) || *end=='<' || *end=='=' || *end=='>' ) break;
         end++;
     }
     if ( !*end ) _parse_binom_expr_error(str);
@@ -176,7 +176,7 @@ void parse_binom_expr(args_t *args, char *str)
     int tag_id = bcf_hdr_id2int(args->in_hdr,BCF_DT_ID,args->binom_tag);
     if ( !bcf_hdr_idinfo_exists(args->in_hdr,BCF_HL_FMT,tag_id) ) error("The FORMAT tag \"%s\" is not present in the VCF\n", args->binom_tag);
 
-    while ( *end && isspace(*end) ) end++;
+    while ( *end && isspace_c(*end) ) end++;
     if ( !*end ) _parse_binom_expr_error(str);
 
     if ( !strncmp(end,"<=",2) ) { args->binom_cmp = cmp_le; beg = end+2; }
@@ -187,11 +187,11 @@ void parse_binom_expr(args_t *args, char *str)
     else if ( !strncmp(end,"=",1) ) { args->binom_cmp = cmp_eq; beg = end+1; }
     else _parse_binom_expr_error(str);
 
-    while ( *beg && isspace(*beg) ) beg++;
+    while ( *beg && isspace_c(*beg) ) beg++;
     if ( !*beg ) _parse_binom_expr_error(str);
 
     args->binom_val = strtod(beg, &end);
-    while ( *end && isspace(*end) ) end++;
+    while ( *end && isspace_c(*end) ) end++;
     if ( *end ) _parse_binom_expr_error(str);
 
     args->tgt_mask |= GT_BINOM;
diff --git a/plugins/split-vep.c b/plugins/split-vep.c
index 1a34bef4e..d0ac6433d 100644
--- a/plugins/split-vep.c
+++ b/plugins/split-vep.c
@@ -341,7 +341,7 @@ static void expand_csq_expression(args_t *args, kstring_t *str)
     char *ptr = strstr(args->format_str,str->s);
     if ( !ptr ) return;
     char *end = ptr + str->l, tmp = *end;
-    if ( isalnum(tmp) || tmp=='_' || tmp=='.' ) return;
+    if ( isalnum_c(tmp) || tmp=='_' || tmp=='.' ) return;
     *end = 0;
 
     str->l = 0;
@@ -396,11 +396,11 @@ static void init_column2type(args_t *args)
         tmp.l = 0;
         kputc('^',&tmp);
         char *ptr = type[i];
-        while ( *ptr && !isspace(*ptr) ) ptr++;
+        while ( *ptr && !isspace_c(*ptr) ) ptr++;
         if ( !*ptr ) error("Error: failed to parse the column type \"%s\"\n",type[i]);
         kputsn(type[i],ptr-type[i],&tmp);
         kputc('$',&tmp);
-        while ( *ptr && isspace(*ptr) ) ptr++;
+        while ( *ptr && isspace_c(*ptr) ) ptr++;
         if ( !*ptr ) error("Error: failed to parse the column type \"%s\"\n",type[i]);
         args->ncolumn2type++;
         args->column2type = (col2type_t*) realloc(args->column2type,sizeof(*args->column2type)*args->ncolumn2type);
@@ -463,7 +463,7 @@ static int query_has_field(char *fmt, char *field, kstring_t *str)
         ptr = strstr(ptr,str->s);
         if ( !ptr ) return 0;
         end = ptr[str->l];
-        if ( isalnum(end) || end=='_' || end=='.' )
+        if ( isalnum_c(end) || end=='_' || end=='.' )
         {
             ptr++;
             continue;
@@ -948,13 +948,13 @@ static void init_data(args_t *args)
     {
         if ( *ep=='#' )
         {
-            while ( *ep && *ep!='\n' ) { *ep = tolower(*ep); ep++; }
+            while ( *ep && *ep!='\n' ) { *ep = tolower_c(*ep); ep++; }
             if ( !*ep ) break;
             ep++;
             continue;
         }
         char *bp = ep;
-        while ( *ep && !isspace(*ep) ) { *ep = tolower(*ep); ep++; }
+        while ( *ep && !isspace_c(*ep) ) { *ep = tolower_c(*ep); ep++; }
         char tmp = *ep;
         *ep = 0;
         args->nscale++;
@@ -965,7 +965,7 @@ static void init_data(args_t *args)
         if ( !tmp ) break;
         if ( tmp=='\n' ) severity++;
         ep++;
-        while ( *ep && isspace(*ep) ) ep++;
+        while ( *ep && isspace_c(*ep) ) ep++;
     }
 
     // Transcript and consequence selection
@@ -1098,7 +1098,7 @@ static void csq_to_severity(args_t *args, char *csq, int *min_severity, int *max
     while ( *ep )
     {
         char *bp = ep;
-        while ( *ep && *ep!='&' ) { *ep = tolower(*ep); ep++; }
+        while ( *ep && *ep!='&' ) { *ep = tolower_c(*ep); ep++; }
         char tmp = *ep;
         *ep = 0;
 
diff --git a/plugins/split.c b/plugins/split.c
index 93d04a971..bbab6a666 100644
--- a/plugins/split.c
+++ b/plugins/split.c
@@ -203,7 +203,7 @@ void init_subsets(args_t *args)
             while ( *ptr )
             {
                 if ( *ptr=='\\' && !escaped ) { escaped = 1; ptr++; continue; }
-                if ( isspace(*ptr) && !escaped ) break;
+                if ( isspace_c(*ptr) && !escaped ) break;
                 if ( *ptr==',' ) set->nsmpl++;      // todo: allow commas in sample names
                 kputc(*ptr, &str);
                 escaped = 0;
@@ -228,16 +228,16 @@ void init_subsets(args_t *args)
             }
             if ( !j ) continue;
 
-            while ( *ptr && isspace(*ptr) ) ptr++;
+            while ( *ptr && isspace_c(*ptr) ) ptr++;
             j = 0;
             if ( *ptr )     // optional second column with new sample names
             {
                 set->rename = (char**) calloc(set->nsmpl, sizeof(*set->rename));
                 beg = ptr;
-                while ( *beg && !isspace(*beg) )
+                while ( *beg && !isspace_c(*beg) )
                 {
                     ptr = beg;
-                    while ( *ptr && *ptr!=',' && !isspace(*ptr) ) ptr++;
+                    while ( *ptr && *ptr!=',' && !isspace_c(*ptr) ) ptr++;
                     char tmp = *ptr;
                     *ptr = 0;
                     if ( !strcmp("-",beg) )
@@ -248,7 +248,7 @@ void init_subsets(args_t *args)
                     }
                     set->rename[j++] = strdup(beg);
                     *ptr = tmp;
-                    if ( !tmp || isspace(tmp) ) break;
+                    if ( !tmp || isspace_c(tmp) ) break;
                     beg = ptr + 1;
                     if ( j >= set->nsmpl )
                         error("Expected the same number of samples in the first and second column: %s\n",files[i]);
@@ -262,7 +262,7 @@ void init_subsets(args_t *args)
                 }
             }
 
-            while ( *ptr && isspace(*ptr) ) ptr++;
+            while ( *ptr && isspace_c(*ptr) ) ptr++;
             if ( *ptr )     // optional third column with file name
             {
                 free(set->fname);
@@ -293,7 +293,7 @@ void init_subsets(args_t *args)
             while ( *ptr )
             {
                 if ( *ptr=='\\' && !escaped ) { escaped = 1; ptr++; continue; }
-                if ( isspace(*ptr) && !escaped ) break;
+                if ( isspace_c(*ptr) && !escaped ) break;
                 escaped = 0;
                 ptr++;
             }
@@ -311,18 +311,18 @@ void init_subsets(args_t *args)
             if ( tmp )      // two columns: new sample name
             {
                 rename = ptr + 1;
-                while ( *rename && isspace(*rename) ) rename++;
+                while ( *rename && isspace_c(*rename) ) rename++;
                 if ( !*rename ) rename = NULL;  // trailing space
                 else
                 {
                     ptr = rename;
-                    while ( *ptr && !isspace(*ptr) ) ptr++;
+                    while ( *ptr && !isspace_c(*ptr) ) ptr++;
                     tmp = *ptr;
                     *ptr = 0;
                     if ( !strcmp("-",rename) ) rename = NULL;
                     if ( tmp ) ptr++;
                 }
-                while ( *ptr && isspace(*ptr) ) ptr++;
+                while ( *ptr && isspace_c(*ptr) ) ptr++;
             }
 
             if ( !*ptr )    // no third column, use sample name as file name
diff --git a/plugins/vrfs.c b/plugins/vrfs.c
index e851003fa..eaddbdaaa 100644
--- a/plugins/vrfs.c
+++ b/plugins/vrfs.c
@@ -161,12 +161,12 @@ static int parse_sites(const char *line, char **chr_beg, char **chr_end, uint32_
 
     // CHR part
     char *ss = (char*) line;
-    while ( *ss && isspace(*ss) ) ss++;
+    while ( *ss && isspace_c(*ss) ) ss++;
     if ( !*ss ) return -1;      // skip blank lines
     if ( *ss=='#' ) return -1;  // skip comments
 
     char *se = ss;
-    while ( *se && !isspace(*se) ) se++;
+    while ( *se && !isspace_c(*se) ) se++;
 
     *chr_beg = ss;
     *chr_end = se-1;
@@ -180,9 +180,9 @@ static int parse_sites(const char *line, char **chr_beg, char **chr_end, uint32_
     (*beg)--;
 
     // REF part and REF length
-    while ( *se && isspace(*se) ) se++;
+    while ( *se && isspace_c(*se) ) se++;
     ss = se;
-    while ( *se && !isspace(*se) ) se++;
+    while ( *se && !isspace_c(*se) ) se++;
     int ref_len = se - ss;
     if ( !ref_len ) error("Could not parse the REF part of the line: %s\n",line);
     *end = *beg;    // we are interested in overlaps at the POS only, not variant length
@@ -195,9 +195,9 @@ static int parse_sites(const char *line, char **chr_beg, char **chr_end, uint32_
     site->dist = calloc(args->profile.nbins,sizeof(*site->dist));
 
     // ALT part
-    while ( *se && isspace(*se) ) se++;
+    while ( *se && isspace_c(*se) ) se++;
     ss = se;
-    while ( *se && !isspace(*se) ) se++;
+    while ( *se && !isspace_c(*se) ) se++;
     int alt_len = se - ss;
     if ( !alt_len ) error("Could not parse the ALT part of the line: %s\n",line);
     site->alt = malloc(alt_len+1);
@@ -738,7 +738,7 @@ static double *parse_float_array(const char *line, int *narray)
     const char *ptr = line;
     while ( *ptr )
     {
-        while ( *ptr && !isspace(*ptr) ) ptr++;
+        while ( *ptr && !isspace_c(*ptr) ) ptr++;
         n++;
         if ( *ptr ) ptr++;
     }
@@ -748,7 +748,7 @@ static double *parse_float_array(const char *line, int *narray)
     {
         char *tmp;
         array[i] = strtod(ptr,&tmp);
-        if ( *tmp && !isspace(*tmp) ) error("Could not parse the float array: %s\n",line);
+        if ( *tmp && !isspace_c(*tmp) ) error("Could not parse the float array: %s\n",line);
         ptr = tmp+1;
     }
     *narray = n;
@@ -771,11 +771,11 @@ static int parse_batch(const char *line, char **chr_beg, char **chr_end, uint32_
 
     // CHR part
     char *ss = (char*) line + 5;
-    while ( *ss && isspace(*ss) ) ss++;
+    while ( *ss && isspace_c(*ss) ) ss++;
     if ( !*ss ) return -2;      // unexpected format
 
     char *se = ss;
-    while ( *se && !isspace(*se) ) se++;
+    while ( *se && !isspace_c(*se) ) se++;
 
     *chr_beg = ss;
     *chr_end = se-1;
@@ -790,7 +790,7 @@ static int parse_batch(const char *line, char **chr_beg, char **chr_end, uint32_
 
     // REF part
     ss = ++se;
-    while ( *se && !isspace(*se) ) se++;
+    while ( *se && !isspace_c(*se) ) se++;
     int ref_len = se - ss;
     *end = *beg;
 
@@ -802,18 +802,18 @@ static int parse_batch(const char *line, char **chr_beg, char **chr_end, uint32_
 
     // ALT part
     ss = ++se;
-    while ( *se && !isspace(*se) ) se++;
+    while ( *se && !isspace_c(*se) ) se++;
     int alt_len = se - ss;
     site->alt = malloc(alt_len+1);
     strncpy(site->alt,ss,alt_len);
     site->alt[alt_len] = 0;
 
     // skip the SCORE part
-    while ( *se && isspace(*se) ) se++;
+    while ( *se && isspace_c(*se) ) se++;
     ss = se;
-    while ( *se && !isspace(*se) ) se++;
+    while ( *se && !isspace_c(*se) ) se++;
     if ( !*se ) error("Could not parse the SCORE part of the line: %s\n",line);
-    while ( *se && isspace(*se) ) se++;
+    while ( *se && isspace_c(*se) ) se++;
     if ( !*se ) error("Could not parse the SCORE part of the line: %s\n",line);
 
     // read the PROFILE part
diff --git a/regidx.c b/regidx.c
index 445d7d585..40d909896 100644
--- a/regidx.c
+++ b/regidx.c
@@ -29,6 +29,9 @@
 #include <htslib/khash_str2int.h>
 #include "regidx.h"
 
+// Avoid having to include all of bcftools.h
+static inline int isspace_c(char c) { return isspace((unsigned char) c); }
+
 #define MAX_COOR_0 REGIDX_MAX   // CSI and hts_itr_query limit, 0-based
 
 #define iBIN(x) ((x)>>13)
@@ -211,13 +214,13 @@ regidx_t *regidx_init_string(const char *str, regidx_parse_f parser, regidx_free
     const char *ss = str;
     while ( *ss )
     {
-        while ( *ss && isspace(*ss) ) ss++;
+        while ( *ss && isspace_c(*ss) ) ss++;
         const char *se = ss;
         while ( *se && *se!='\r' && *se!='\n' ) se++;
         tmp.l = 0;
         kputsn(ss, se-ss, &tmp);
         regidx_insert(idx,tmp.s);
-        while ( *se && isspace(*se) ) se++;
+        while ( *se && isspace_c(*se) ) se++;
         ss = se;
     }
     free(tmp.s);
@@ -476,12 +479,12 @@ int regidx_overlap(regidx_t *regidx, const char *chr, uint32_t beg, uint32_t end
 int regidx_parse_bed(const char *line, char **chr_beg, char **chr_end, uint32_t *beg, uint32_t *end, void *payload, void *usr)
 {
     char *ss = (char*) line;
-    while ( *ss && isspace(*ss) ) ss++;
+    while ( *ss && isspace_c(*ss) ) ss++;
     if ( !*ss ) return -1;      // skip blank lines
     if ( *ss=='#' ) return -1;  // skip comments
 
     char *se = ss;
-    while ( *se && !isspace(*se) ) se++;
+    while ( *se && !isspace_c(*se) ) se++;
 
     *chr_beg = ss;
     *chr_end = se-1;
@@ -508,12 +511,12 @@ int regidx_parse_bed(const char *line, char **chr_beg, char **chr_end, uint32_t
 int regidx_parse_tab(const char *line, char **chr_beg, char **chr_end, uint32_t *beg, uint32_t *end, void *payload, void *usr)
 {
     char *ss = (char*) line;
-    while ( *ss && isspace(*ss) ) ss++;
+    while ( *ss && isspace_c(*ss) ) ss++;
     if ( !*ss ) return -1;      // skip blank lines
     if ( *ss=='#' ) return -1;  // skip comments
 
     char *se = ss;
-    while ( *se && !isspace(*se) ) se++;
+    while ( *se && !isspace_c(*se) ) se++;
 
     *chr_beg = ss;
     *chr_end = se-1;
@@ -538,7 +541,7 @@ int regidx_parse_tab(const char *line, char **chr_beg, char **chr_end, uint32_t
     {
         ss = se+1;
         *end = strtod(ss, &se);
-        if ( ss==se || (*se && !isspace(*se)) ) *end = *beg;
+        if ( ss==se || (*se && !isspace_c(*se)) ) *end = *beg;
         else if ( *end==0 ) { fprintf(stderr,"Could not parse tab line, expected 1-based coordinate: %s\n", line); return -2; }
         else (*end)--;
     }
@@ -555,7 +558,7 @@ int regidx_parse_vcf(const char *line, char **chr_beg, char **chr_end, uint32_t
 int regidx_parse_reg(const char *line, char **chr_beg, char **chr_end, uint32_t *beg, uint32_t *end, void *payload, void *usr)
 {
     char *ss = (char*) line;
-    while ( *ss && isspace(*ss) ) ss++;
+    while ( *ss && isspace_c(*ss) ) ss++;
     if ( !*ss ) return -1;      // skip blank lines
     if ( *ss=='#' ) return -1;  // skip comments
 
diff --git a/reheader.c b/reheader.c
index df631aae3..bb94e7a22 100644
--- a/reheader.c
+++ b/reheader.c
@@ -78,10 +78,10 @@ static char *copy_and_update_contig_line(faidx_t *fai, char *line, void *chr_see
         p = ++q;
         while ( *q && (*q==' ' || *q=='\t') ) { p++; q++; }
         // ^[A-Za-z_][0-9A-Za-z_.]*$
-        if (p==q && *q && (isalpha(*q) || *q=='_'))
+        if (p==q && *q && (isalpha_c(*q) || *q=='_'))
         {
             q++;
-            while ( *q && (isalnum(*q) || *q=='_' || *q=='.') ) q++;
+            while ( *q && (isalnum_c(*q) || *q=='_' || *q=='.') ) q++;
         }
         int n = q-p;
         int m = 0;
@@ -228,7 +228,7 @@ static void read_header_file(char *fname, kstring_t *hdr)
     if ( hts_close(fp) ) error("Close failed: %s\n", fname);
     free(tmp.s);
 
-    while ( hdr->l>0 && isspace(hdr->s[hdr->l-1]) ) hdr->l--;  // remove trailing newlines
+    while ( hdr->l>0 && isspace_c(hdr->s[hdr->l-1]) ) hdr->l--;  // remove trailing newlines
     kputc('\n',hdr);
 }
 
@@ -248,17 +248,17 @@ static int set_sample_pairs(char **samples, int nsamples, kstring_t *hdr, int id
         while ( *ptr )
         {
             if ( *ptr=='\\' && !escaped ) { escaped = 1; ptr++; continue; }
-            if ( isspace(*ptr) && !escaped ) break;
+            if ( isspace_c(*ptr) && !escaped ) break;
             kputc(*ptr, &key);
             escaped = 0;
             ptr++;
         }
         if ( !*ptr ) break;
-        while ( *ptr && isspace(*ptr) ) ptr++;
+        while ( *ptr && isspace_c(*ptr) ) ptr++;
         while ( *ptr )
         {
             if ( *ptr=='\\' && !escaped ) { escaped = 1; ptr++; continue; }
-            if ( isspace(*ptr) && !escaped ) break;
+            if ( isspace_c(*ptr) && !escaped ) break;
             kputc(*ptr, &val);
             escaped = 0;
             ptr++;
@@ -273,7 +273,7 @@ static int set_sample_pairs(char **samples, int nsamples, kstring_t *hdr, int id
         return 0;
     }
 
-    while ( hdr->l>0 && isspace(hdr->s[hdr->l-1]) ) hdr->l--;  // remove trailing newlines
+    while ( hdr->l>0 && isspace_c(hdr->s[hdr->l-1]) ) hdr->l--;  // remove trailing newlines
     hdr->s[hdr->l] = 0;
 
     kstring_t tmp = {0,0,0};
diff --git a/smpl_ilist.c b/smpl_ilist.c
index 4bc4cec2e..7a0d5e275 100644
--- a/smpl_ilist.c
+++ b/smpl_ilist.c
@@ -40,7 +40,7 @@ void smpl_ilist_destroy(smpl_ilist_t *smpl)
 
 static inline int is_space_or_escaped(const char *min, const char *str)
 {
-    if ( !isspace(*str) ) return 0;
+    if ( !isspace_c(*str) ) return 0;
     int n = 0;
     while ( --str>=min && *str=='\\' ) n++;
     return n%2 ? 0 : 1;
diff --git a/str_finder.c b/str_finder.c
index a9281d811..cf9e4bdf9 100644
--- a/str_finder.c
+++ b/str_finder.c
@@ -94,7 +94,7 @@ static void add_rep(rep_ele **list, char *cons, int clen, int pos, int rlen,
     if (lower_only) {
 	int lc = 0;
 	for (i = el->start; i <= el->end; i++) {
-	    if (islower(cons[i])) {
+	    if (islower((unsigned char) cons[i])) {
 		lc = 1;
 		break;
 	    }
diff --git a/test/test-regidx.c b/test/test-regidx.c
index eed36ab74..8ec261d61 100644
--- a/test/test-regidx.c
+++ b/test/test-regidx.c
@@ -37,6 +37,9 @@
 #include <time.h>
 #include "regidx.h"
 
+// Avoid having to include all of bcftools.h
+static inline int isspace_c(char c) { return isspace((unsigned char) c); }
+
 static int verbose = 0;
 
 void HTS_FORMAT(HTS_PRINTF_FMT, 1, 2)
@@ -75,18 +78,18 @@ int custom_parse(const char *line, char **chr_beg, char **chr_end, uint32_t *beg
 
     // Skip the fields that were parsed above
     char *ss = (char*) line;
-    while ( *ss && isspace(*ss) ) ss++;
+    while ( *ss && isspace_c(*ss) ) ss++;
     for (i=0; i<3; i++)
     {
-        while ( *ss && !isspace(*ss) ) ss++;
+        while ( *ss && !isspace_c(*ss) ) ss++;
         if ( !*ss ) return -2;  // wrong number of fields
-        while ( *ss && isspace(*ss) ) ss++;
+        while ( *ss && isspace_c(*ss) ) ss++;
     }
     if ( !*ss ) return -2;
 
     // Parse the payload
     char *se = ss;
-    while ( *se && !isspace(*se) ) se++;
+    while ( *se && !isspace_c(*se) ) se++;
     char **dat = (char**) payload;
     *dat = (char*) malloc(se-ss+1);
     memcpy(*dat,ss,se-ss+1);
diff --git a/tsv2vcf.c b/tsv2vcf.c
index 22dec3065..89b972088 100644
--- a/tsv2vcf.c
+++ b/tsv2vcf.c
@@ -79,14 +79,14 @@ int tsv_parse(tsv_t *tsv, bcf1_t *rec, char *str)
     tsv->ss = tsv->se = str;
     while ( *tsv->ss && tsv->icol < tsv->ncols )
     {
-        while ( *tsv->se && !isspace(*tsv->se) ) tsv->se++;
+        while ( *tsv->se && !isspace_c(*tsv->se) ) tsv->se++;
         if ( tsv->cols[tsv->icol].setter )
         {
             int ret = tsv->cols[tsv->icol].setter(tsv,rec,tsv->cols[tsv->icol].usr);
             if ( ret<0 ) return -1;
             status++;
         }
-        while ( *tsv->se && isspace(*tsv->se) ) tsv->se++;
+        while ( *tsv->se && isspace_c(*tsv->se) ) tsv->se++;
         tsv->ss = tsv->se;
         tsv->icol++;
     }
@@ -123,7 +123,7 @@ int tsv_setter_ref_alt(tsv_t *tsv, bcf1_t *rec, void *usr)
 {
     bcf_hdr_t *hdr = (bcf_hdr_t*)usr;
     char *sb = tsv->ss;
-    while ( *sb && !isspace(*sb) ) sb++;
+    while ( *sb && !isspace_c(*sb) ) sb++;
     if ( !*sb ) return -1;
     char tmp = *sb;
     *sb = ',';
diff --git a/tsv2vcf.h b/tsv2vcf.h
index 68757d459..53964adcf 100644
--- a/tsv2vcf.h
+++ b/tsv2vcf.h
@@ -27,6 +27,7 @@
 #define __TSV2VCF_H__
 
 #include <htslib/vcf.h>
+#include "bcftools.h"
 
 typedef struct _tsv_t tsv_t;
 typedef int (*tsv_setter_t)(tsv_t *, bcf1_t *, void *);
@@ -65,12 +66,12 @@ static inline int tsv_next(tsv_t *tsv)
     if ( !*tsv->se ) return -1;
     if ( tsv->ss==tsv->se )
     {
-        while ( *tsv->se && !isspace(*tsv->se) ) tsv->se++;
+        while ( *tsv->se && !isspace_c(*tsv->se) ) tsv->se++;
         return 0;
     }
-    while ( *tsv->se && isspace(*tsv->se) ) tsv->se++;
+    while ( *tsv->se && isspace_c(*tsv->se) ) tsv->se++;
     tsv->ss = tsv->se;
-    while ( *tsv->se && !isspace(*tsv->se) ) tsv->se++;
+    while ( *tsv->se && !isspace_c(*tsv->se) ) tsv->se++;
     return 0;
 }
 
diff --git a/vcfannotate.c b/vcfannotate.c
index 7e19fe0f1..47e70d82f 100644
--- a/vcfannotate.c
+++ b/vcfannotate.c
@@ -2229,12 +2229,12 @@ static void init_columns(args_t *args)
         for (i=0; i<n; i++)
         {
             char *ptr = str[i];
-            while ( *ptr && !isspace(*ptr) ) ptr++;
+            while ( *ptr && !isspace_c(*ptr) ) ptr++;
             if ( *ptr )
             {
                 *ptr = 0;
                 ptr++;
-                while ( *ptr && isspace(*ptr) ) ptr++;
+                while ( *ptr && isspace_c(*ptr) ) ptr++;
                 if ( *ptr )
                 {
                     if ( args->merge_method_str.l ) kputc(',',&args->merge_method_str);
@@ -2834,7 +2834,7 @@ static void rename_chrs(args_t *args, char *fname)
     for (i=0; i<n; i++)
     {
         char *ss = map[i];
-        while ( *ss && !isspace(*ss) ) ss++;
+        while ( *ss && !isspace_c(*ss) ) ss++;
         if ( !*ss ) error("Could not parse: %s\n", fname);
         *ss = 0;
         int rid = bcf_hdr_name2id(args->hdr_out, map[i]);
@@ -2844,9 +2844,9 @@ static void rename_chrs(args_t *args, char *fname)
         assert( j>=0 );
         free(hrec->vals[j]);
         ss++;
-        while ( *ss && isspace(*ss) ) ss++;
+        while ( *ss && isspace_c(*ss) ) ss++;
         char *se = ss;
-        while ( *se && !isspace(*se) ) se++;
+        while ( *se && !isspace_c(*se) ) se++;
         *se = 0;
         hrec->vals[j] = strdup(ss);
         args->hdr_out->id[BCF_DT_CTG][rid].key = hrec->vals[j];
@@ -2891,7 +2891,7 @@ static int rename_annots_core(args_t *args, char *ori_tag, char *new_tag)
     assert( j>=0 );
     free(hrec->vals[j]);
     char *ptr = new_tag;
-    while ( *ptr && !isspace(*ptr) ) ptr++;
+    while ( *ptr && !isspace_c(*ptr) ) ptr++;
     *ptr = 0;
     hrec->vals[j] = strdup(new_tag);
     args->hdr_out->id[BCF_DT_ID][id].key = hrec->vals[j];
@@ -2908,12 +2908,12 @@ static void rename_annots(args_t *args)
     for (i=0; i<args->rename_annots_nmap; i++)
     {
         char *ptr = args->rename_annots_map[i];
-        while ( *ptr && !isspace(*ptr) ) ptr++;
+        while ( *ptr && !isspace_c(*ptr) ) ptr++;
         if ( !*ptr ) error("Could not parse: %s\n", args->rename_annots_map[i]);
         char *rmme = ptr;
         *ptr = 0;
         ptr++;
-        while ( *ptr && isspace(*ptr) ) ptr++;
+        while ( *ptr && isspace_c(*ptr) ) ptr++;
         if ( !*ptr ) { *rmme = ' '; error("Could not parse: %s\n", args->rename_annots_map[i]); }
         if ( rename_annots_core(args, args->rename_annots_map[i], ptr) < 0 )
             error("Cannot rename \"%s\" to \"%s\"\n",args->rename_annots_map[i],ptr);
diff --git a/vcfcall.c b/vcfcall.c
index 7ea143666..063332b40 100644
--- a/vcfcall.c
+++ b/vcfcall.c
@@ -218,11 +218,11 @@ static char **parse_ped_samples(args_t *args, call_t *call, char **vals, int nva
         j = 0;
         while ( *tmp && j<5 )
         {
-            if ( isspace(*tmp) )
+            if ( isspace_c(*tmp) )
             {
                 *tmp = 0;
                 ++tmp;
-                while ( isspace(*tmp) ) tmp++;  // allow multiple spaces
+                while ( isspace_c(*tmp) ) tmp++;  // allow multiple spaces
                 col_ends[j] = tmp-1;
                 j++;
                 continue;
@@ -312,11 +312,11 @@ static void set_samples(args_t *args, const char *fn, int is_file)
         for (i=0; i<nlines; i++)
         {
             char *ss = lines[i];
-            while ( *ss && isspace(*ss) ) ss++;
+            while ( *ss && isspace_c(*ss) ) ss++;
             if ( !*ss ) error("Could not parse: %s\n", lines[i]);
             if ( *ss=='#' ) continue;
             char *se = ss;
-            while ( *se && !isspace(*se) ) se++;
+            while ( *se && !isspace_c(*se) ) se++;
             char x = *se, *xptr = se; *se = 0;
 
             int ismpl = bcf_hdr_id2int(args->aux.hdr, BCF_DT_SAMPLE, ss);
@@ -324,10 +324,10 @@ static void set_samples(args_t *args, const char *fn, int is_file)
             if ( old2new[ismpl] != -1 ) { fprintf(stderr,"Warning: The sample is listed multiple times: %s\n",ss); continue; }
 
             ss = se+(x != '\0');
-            while ( *ss && isspace(*ss) ) ss++;
+            while ( *ss && isspace_c(*ss) ) ss++;
             if ( !*ss ) ss = "2";   // default ploidy
             se = ss;
-            while ( *se && !isspace(*se) ) se++;
+            while ( *se && !isspace_c(*se) ) se++;
             if ( se==ss ) { *xptr = x; error("Could not parse: \"%s\"\n", lines[i]); }
 
             char *sex = ss;
@@ -354,11 +354,11 @@ static void set_samples(args_t *args, const char *fn, int is_file)
         for (i=0; i<nlines; i++)
         {
             char *ss = lines[i];
-            while ( *ss && isspace(*ss) ) ss++;
+            while ( *ss && isspace_c(*ss) ) ss++;
             if ( !*ss ) error("Could not parse: %s\n", lines[i]);
             if ( *ss=='#' ) continue;
             char *se = ss;
-            while ( *se && !isspace(*se) ) se++;
+            while ( *se && !isspace_c(*se) ) se++;
             *se = 0;
 
             int ismpl = bcf_hdr_id2int(args->aux.hdr, BCF_DT_SAMPLE, ss);
@@ -416,12 +416,12 @@ static void init_missed_line(args_t *args)
 static int tgt_parse(const char *line, char **chr_beg, char **chr_end, uint32_t *beg, uint32_t *end, void *payload, void *usr)
 {
     char *ss = (char*) line;
-    while ( *ss && isspace(*ss) ) ss++;
+    while ( *ss && isspace_c(*ss) ) ss++;
     if ( !*ss ) { fprintf(stderr,"Could not parse the line: %s\n", line); return -2; }
     if ( *ss=='#' ) return -1;  // skip comments
 
     char *se = ss;
-    while ( *se && !isspace(*se) ) se++;
+    while ( *se && !isspace_c(*se) ) se++;
 
     *chr_beg = ss;
     *chr_end = se-1;
@@ -445,14 +445,14 @@ static int tgt_parse(const char *line, char **chr_beg, char **chr_end, uint32_t
     while ( *ss )
     {
         se = ss;
-        while ( *se && *se!=',' && !isspace(*se) ) se++;
+        while ( *se && *se!=',' && !isspace_c(*se) ) se++;
         als->n++;
         als->allele = (char**)realloc(als->allele,als->n*sizeof(*als->allele));
         als->allele[als->n-1] = (char*)malloc(se-ss+1);
         memcpy(als->allele[als->n-1],ss,se-ss);
         als->allele[als->n-1][se-ss] = 0;
         ss = se+1;
-        if ( !*se || isspace(*se) ) break;
+        if ( !*se || isspace_c(*se) ) break;
     }
     if ( als->n<2 ) error("Unable to parse the -T file; expected CHROM\\tPOS\\tREF,ALT with -C alleles but found instead:\n\t%s\n",line);
     return 0;
diff --git a/vcfconvert.c b/vcfconvert.c
index b01742ae6..db09166a5 100644
--- a/vcfconvert.c
+++ b/vcfconvert.c
@@ -201,8 +201,8 @@ static int _set_chrom_pos_ref_alt(tsv_t *tsv, bcf1_t *rec, void *usr)
     if ( *se!='_' ) return -1;
     kputsn(ss,se-ss,&args->str);
     ss = ++se;
-    while ( se < tsv->se && *se!='_' && isspace(*tsv->se) ) se++;
-    if ( se < tsv->se && *se!='_' && isspace(*tsv->se) ) return -1;
+    while ( se < tsv->se && *se!='_' && isspace_c(*tsv->se) ) se++;
+    if ( se < tsv->se && *se!='_' && isspace_c(*tsv->se) ) return -1;
     kputc(',',&args->str);
     kputsn(ss,se-ss,&args->str);
 
@@ -275,9 +275,9 @@ static int tsv_setter_verify_ref_alt(tsv_t *tsv, bcf1_t *rec, void *usr)
         args->rev_als = 1;
     }
     *tsv->se = tmp;
-    while ( *tsv->se && isspace(*tsv->se) ) tsv->se++;
+    while ( *tsv->se && isspace_c(*tsv->se) ) tsv->se++;
     tsv->ss = tsv->se;
-    while ( *tsv->se && !isspace(*tsv->se) ) tsv->se++;
+    while ( *tsv->se && !isspace_c(*tsv->se) ) tsv->se++;
     tmp = *tsv->se; *tsv->se = 0;
     if ( !args->rev_als && strcmp(tsv->ss,rec->d.allele[1]) ) { *tsv->se = tmp; error("REF/ALT mismatch: [%s][%s]\n", tsv->ss,rec->d.allele[1]); }
     else if ( args->rev_als && strcmp(tsv->ss,rec->d.allele[0]) ) { *tsv->se = tmp; error("REF/ALT mismatch: [%s][%s]\n", tsv->ss,rec->d.allele[0]); }
@@ -436,7 +436,7 @@ static void gensample_to_vcf(args_t *args)
     // of the columns (CHROM:POS_REF_ALT comes first or second)
     args->str.l = 0;
     char *sb = line.s, *se = line.s;
-    while ( *se && !isspace(*se) ) se++;
+    while ( *se && !isspace_c(*se) ) se++;
     if ( !*se ) error("Could not determine CHROM in %s: %s\n", gen_fname,line.s);
     if ( args->gen_3N6 )    // first column, just CHROM
         kputsn(sb, se-sb, &args->str);
@@ -445,7 +445,7 @@ static void gensample_to_vcf(args_t *args)
         char *sc = strchr(sb,':');
         if ( !sc || sc > se )
         {
-            while ( *se && !isspace(*se) ) se++;
+            while ( *se && !isspace_c(*se) ) se++;
             if ( !*se ) error("Could not determine CHROM in %s: %s\n", gen_fname,line.s);
             sb = ++se;
             sc = strchr(sb,':');
@@ -482,7 +482,7 @@ static void gensample_to_vcf(args_t *args)
     if ( !samples ) error("Could not read %s\n", sample_fname);
     for (i=2; i<nsamples; i++)
     {
-        se = samples[i]; while ( *se && !isspace(*se) ) se++;
+        se = samples[i]; while ( *se && !isspace_c(*se) ) se++;
         *se = 0;
         bcf_hdr_add_sample(args->header,samples[i]);
     }
@@ -627,7 +627,7 @@ static void haplegendsample_to_vcf(args_t *args)
     // returned from hts_readlist (i=1, and not i=0)
     for (i=1; i<nrows; i++)
     {
-        se = samples[i]; while ( *se && !isspace(*se) ) se++;
+        se = samples[i]; while ( *se && !isspace_c(*se) ) se++;
         *se = 0;
         bcf_hdr_add_sample(args->header,samples[i]);
     }
@@ -736,13 +736,13 @@ static void hapsample_to_vcf(args_t *args)
     // Find out the chromosome name, it can be either in the first or second column
     args->str.l = 0;
     char *sb = line.s, *se = line.s;
-    while ( *se && !isspace(*se) ) se++;
+    while ( *se && !isspace_c(*se) ) se++;
     if ( !*se ) error("Could not determine CHROM in %s: %s\n", hap_fname,line.s);
     if ( !args->output_vcf_ids )
     {
         // first column should be just CHROM, but the second must be CHROM:POS_REF_ALT, use that
         sb = ++se;
-        while ( *se && !isspace(*se) ) se++;
+        while ( *se && !isspace_c(*se) ) se++;
         if ( !*se ) error("Could not determine CHROM in %s: %s\n", hap_fname,line.s);
         if ( !strchr(sb,':') )
             error("Could not determine CHROM in the second column of %s: %s\n", hap_fname,line.s);
@@ -781,7 +781,7 @@ static void hapsample_to_vcf(args_t *args)
     if ( !samples ) error("Could not read %s\n", sample_fname);
     for (i=2; i<nsamples; i++)
     {
-        se = samples[i]; while ( *se && !isspace(*se) ) se++;
+        se = samples[i]; while ( *se && !isspace_c(*se) ) se++;
         *se = 0;
         bcf_hdr_add_sample(args->header,samples[i]);
     }
@@ -847,13 +847,13 @@ char *init_sample2sex(bcf_hdr_t *hdr, char *sex_fname)
     if ( !lines ) error("Could not read %s\n", sex_fname);
     for (i=0; i<nlines; i++)
     {
-        char *se = lines[i]; while ( *se && !isspace(*se) ) se++;
+        char *se = lines[i]; while ( *se && !isspace_c(*se) ) se++;
         char tmp = *se;
         *se = 0;
         int id = bcf_hdr_id2int(hdr, BCF_DT_SAMPLE, lines[i]);
         *se = tmp;
         if ( id<0 ) continue;
-        while ( *se && isspace(*se) ) se++;
+        while ( *se && isspace_c(*se) ) se++;
         if ( *se=='M' ) sample2sex[id] = '1';
         else if ( *se=='F' ) sample2sex[id] = '2';
         else error("Could not parse %s: %s\n", sex_fname,lines[i]);
@@ -1300,8 +1300,8 @@ static inline int tsv_setter_aa1(args_t *args, char *ss, char *se, int alleles[]
     if ( ss[0]=='I' ) return -2;    // skip insertions/deletions for now
     if ( ss[0]=='D' ) return -2;
 
-    int a0 = acgt_to_5(toupper(ss[0]));
-    int a1 = ss[1] ? acgt_to_5(toupper(ss[1])) : a0;
+    int a0 = acgt_to_5(toupper_c(ss[0]));
+    int a1 = ss[1] ? acgt_to_5(toupper_c(ss[1])) : a0;
     if ( alleles[a0]<0 ) alleles[a0] = (*nals)++;
     if ( alleles[a1]<0 ) alleles[a1] = (*nals)++;
 
@@ -1325,7 +1325,7 @@ static int tsv_setter_aa(tsv_t *tsv, bcf1_t *rec, void *usr)
     if ( !ref ) error("faidx_fetch_seq failed at %s:%"PRId64"\n", bcf_hdr_id2name(args->header,rec->rid),(int64_t) rec->pos+1);
 
     int nals = 1, alleles[5] = { -1, -1, -1, -1, -1 };    // a,c,g,t,n
-    ref[0] = toupper(ref[0]);
+    ref[0] = toupper_c(ref[0]);
     int iref = acgt_to_5(ref[0]);
     alleles[iref] = 0;
 
diff --git a/vcfgtcheck.c b/vcfgtcheck.c
index d4999f1d4..1ce426ba0 100644
--- a/vcfgtcheck.c
+++ b/vcfgtcheck.c
@@ -359,13 +359,13 @@ static void init_data(args_t *args)
             for (i=0; i<args->npairs; i++)
             {
                 char *ptr = tmp[i];
-                while ( *ptr && !isspace(*ptr) ) ptr++;
+                while ( *ptr && !isspace_c(*ptr) ) ptr++;
                 if ( !*ptr ) error("Could not parse %s: %s\n",args->pair_samples,tmp[i]);
                 *ptr = 0;
                 args->pairs[i].iqry = bcf_hdr_id2int(args->qry_hdr, BCF_DT_SAMPLE, tmp[i]);
                 if ( args->pairs[i].iqry < 0 ) error("No such sample in %s: [%s]\n",args->qry_fname,tmp[i]);
                 ptr++;
-                while ( *ptr && isspace(*ptr) ) ptr++;
+                while ( *ptr && isspace_c(*ptr) ) ptr++;
                 args->pairs[i].igt = bcf_hdr_id2int(args->gt_hdr?args->gt_hdr:args->qry_hdr, BCF_DT_SAMPLE, ptr);
                 if ( args->pairs[i].igt < 0 ) error("No such sample in %s: [%s]\n",args->gt_fname?args->gt_fname:args->qry_fname,ptr);
                 free(tmp[i]);
diff --git a/vcfisec.c b/vcfisec.c
index 51750c170..2b2691a29 100644
--- a/vcfisec.c
+++ b/vcfisec.c
@@ -630,7 +630,7 @@ int main_vcfisec(int argc, char *argv[])
                     else if ( *p=='+' ) { args->isec_op = OP_PLUS; p++; }
                     else if ( *p=='=' ) { args->isec_op = OP_EQUAL; p++; }
                     else if ( *p=='~' ) { args->isec_op = OP_EXACT; p++; }
-                    else if ( isdigit(*p) ) args->isec_op = OP_EQUAL;
+                    else if ( isdigit_c(*p) ) args->isec_op = OP_EQUAL;
                     else error("Could not parse --nfiles %s\n", optarg);
                     if ( args->isec_op == OP_EXACT ) args->isec_exact = p;
                     else if ( sscanf(p,"%d",&args->isec_n)!=1 ) error("Could not parse --nfiles %s\n", optarg);
diff --git a/vcfmerge.c b/vcfmerge.c
index ce6a71c9c..9f1a8e9ea 100644
--- a/vcfmerge.c
+++ b/vcfmerge.c
@@ -793,12 +793,12 @@ char **merge_alleles(char **a, int na, int *map, char **b, int *nb, int *mb)
         for (i=0; i<na; i++)
         {
             int len = strlen(a[i]);
-            for (j=0; j<len; j++) a[i][j] = toupper(a[i][j]);
+            for (j=0; j<len; j++) a[i][j] = toupper_c(a[i][j]);
         }
         for (i=0; i<*nb; i++)
         {
             int len = strlen(b[i]);
-            for (j=0; j<len; j++) b[i][j] = toupper(b[i][j]);
+            for (j=0; j<len; j++) b[i][j] = toupper_c(b[i][j]);
         }
     }
 
diff --git a/vcfnorm.c b/vcfnorm.c
index 4c8604f8b..52c8a9ebb 100644
--- a/vcfnorm.c
+++ b/vcfnorm.c
@@ -177,7 +177,7 @@ static inline int replace_iupac_codes(char *seq, int nseq)
     int i, n = 0;
     for (i=0; i<nseq; i++)
     {
-        char c = toupper(seq[i]);
+        char c = toupper_c(seq[i]);
         if ( c!='A' && c!='C' && c!='G' && c!='T' && c!='N' ) { seq[i] = 'N'; n++; }
     }
     return n;
@@ -187,7 +187,7 @@ static inline int has_non_acgtn(char *seq, int nseq)
     char *end = seq + nseq;
     while ( *seq && seq<end )
     {
-        char c = toupper(*seq);
+        char c = toupper_c(*seq);
         if ( c!='A' && c!='C' && c!='G' && c!='T' && c!='N' ) return 1;
         seq++;
     }
@@ -449,7 +449,7 @@ static hts_pos_t realign_left(args_t *args, bcf1_t *line)
         int min_len = als[0].l;
         for (i=1; i<line->n_allele; i++)
         {
-            if ( toupper(als[0].s[ als[0].l-1 ]) != toupper(als[i].s[ als[i].l-1 ]) ) break;
+            if ( toupper_c(als[0].s[ als[0].l-1 ]) != toupper_c(als[i].s[ als[i].l-1 ]) ) break;
             if ( als[i].l < min_len ) min_len = als[i].l;
         }
         if ( i!=line->n_allele ) break; // there are differences, cannot be trimmed
@@ -490,7 +490,7 @@ static hts_pos_t realign_left(args_t *args, bcf1_t *line)
         int min_len = als[0].l - ntrim_left;
         for (i=1; i<line->n_allele; i++)
         {
-            if ( toupper(als[0].s[ntrim_left]) != toupper(als[i].s[ntrim_left]) ) break;
+            if ( toupper_c(als[0].s[ntrim_left]) != toupper_c(als[i].s[ntrim_left]) ) break;
             if ( min_len > als[i].l - ntrim_left ) min_len = als[i].l - ntrim_left;
         }
         if ( i!=line->n_allele || min_len<=1 ) break; // there are differences, cannot be trimmed
@@ -524,7 +524,7 @@ static hts_pos_t realign_right(args_t *args, bcf1_t *line)
         for (i=1; i<line->n_allele; i++)
         {
             if ( als[0].l!=als[i].l ) has_indel = 1;
-            if ( toupper(als[0].s[ntrim_left]) != toupper(als[i].s[ntrim_left]) ) break;
+            if ( toupper_c(als[0].s[ntrim_left]) != toupper_c(als[i].s[ntrim_left]) ) break;
             if ( min_len > als[i].l - ntrim_left ) min_len = als[i].l - ntrim_left;
         }
         if ( i!=line->n_allele ) break; // there are differences, cannot be trimmed further
@@ -559,7 +559,7 @@ static hts_pos_t realign_right(args_t *args, bcf1_t *line)
         int min_len = als[0].l;
         for (i=1; i<line->n_allele; i++)
         {
-            if ( toupper(als[0].s[ als[0].l-1 ]) != toupper(als[i].s[ als[i].l-1 ]) ) break;
+            if ( toupper_c(als[0].s[ als[0].l-1 ]) != toupper_c(als[i].s[ als[i].l-1 ]) ) break;
             if ( min_len > als[i].l ) min_len = als[i].l;
         }
         if ( i!=line->n_allele || min_len<=1 ) break; // there are differences, cannot be trimmed more
diff --git a/vcfroh.c b/vcfroh.c
index 1b3eff91f..d4da445c1 100644
--- a/vcfroh.c
+++ b/vcfroh.c
@@ -408,7 +408,7 @@ static int load_genmap(args_t *args, const char *chr)
 
         // skip second column
         tmp++;
-        while ( *tmp && !isspace(*tmp) ) tmp++;
+        while ( *tmp && !isspace_c(*tmp) ) tmp++;
 
         // read the genetic map in cM, scale from % to likelihood
         gm->rate = strtod(tmp+1, &end);
@@ -677,9 +677,9 @@ int read_AF(bcf_sr_regions_t *tgt, bcf1_t *line, double *alt_freq)
         str++;
     }
     *alt_freq = strtod(str, &tmp);
-    if ( *tmp && !isspace(*tmp) )
+    if ( *tmp && !isspace_c(*tmp) )
     {
-        if ( str[0]=='.' && (!str[1] || isspace(str[1])) ) return -1; // missing value
+        if ( str[0]=='.' && (!str[1] || isspace_c(str[1])) ) return -1; // missing value
         error("Could not parse: [%s]\n", tgt->line.s);
     }
     if ( *alt_freq<0 || *alt_freq>1 ) error("Could not parse AF: [%s]\n", tgt->line.s);
diff --git a/vcmp.c b/vcmp.c
index dbdc4b7ac..c5f9ec84a 100644
--- a/vcmp.c
+++ b/vcmp.c
@@ -30,6 +30,9 @@ THE SOFTWARE.  */
 #include <ctype.h>
 #include "vcmp.h"
 
+// Avoid having to include all of bcftools.h
+static inline char toupper_c(char c) { return toupper((unsigned char) c); }
+
 struct _vcmp_t
 {
     char *dref;
@@ -57,7 +60,7 @@ int vcmp_set_ref(vcmp_t *vcmp, char *ref1, char *ref2)
     vcmp->ndref = 0;
 
     char *a = ref1, *b = ref2;
-    while ( *a && *b && toupper(*a)==toupper(*b) ) { a++; b++; }
+    while ( *a && *b && toupper_c(*a)==toupper_c(*b) ) { a++; b++; }
     if ( !*a && !*b ) return 0;
     if ( *a && *b ) return -1;  // refs not compatible
 
@@ -68,7 +71,7 @@ int vcmp_set_ref(vcmp_t *vcmp, char *ref1, char *ref2)
         while ( *a ) a++;
         vcmp->ndref = (a-ref1) - vcmp->nmatch;
         hts_expand(char,vcmp->ndref+1,vcmp->mdref,vcmp->dref);
-        for (i=0; i<vcmp->ndref; i++) vcmp->dref[i] = toupper(ref1[vcmp->nmatch+i]);
+        for (i=0; i<vcmp->ndref; i++) vcmp->dref[i] = toupper_c(ref1[vcmp->nmatch+i]);
         vcmp->dref[vcmp->ndref] = 0;
         return 0;
     }
@@ -78,7 +81,7 @@ int vcmp_set_ref(vcmp_t *vcmp, char *ref1, char *ref2)
     while ( *b ) b++;
     vcmp->ndref = (b-ref2) - vcmp->nmatch;
     hts_expand(char,vcmp->ndref+1,vcmp->mdref,vcmp->dref);
-    for (i=0; i<vcmp->ndref; i++) vcmp->dref[i] = toupper(ref2[vcmp->nmatch+i]);
+    for (i=0; i<vcmp->ndref; i++) vcmp->dref[i] = toupper_c(ref2[vcmp->nmatch+i]);
     vcmp->dref[vcmp->ndref] = 0;
     vcmp->ndref *= -1;
     return 0;
@@ -90,7 +93,7 @@ int vcmp_find_allele(vcmp_t *vcmp, char **als1, int nals1, char *al2)
     for (i=0; i<nals1; i++)
     {
         char *a = als1[i], *b = al2;
-        while ( *a && *b && toupper(*a)==toupper(*b) ) { a++; b++; }
+        while ( *a && *b && toupper_c(*a)==toupper_c(*b) ) { a++; b++; }
         if ( *a && *b ) continue;   // mismatch
         if ( !vcmp->ndref )
         {
@@ -103,14 +106,14 @@ int vcmp_find_allele(vcmp_t *vcmp, char **als1, int nals1, char *al2)
         {
             if ( vcmp->ndref<0 ) continue;
             for (j=0; j<vcmp->ndref; j++)
-                if ( !a[j] || toupper(a[j])!=vcmp->dref[j] ) break;
+                if ( !a[j] || toupper_c(a[j])!=vcmp->dref[j] ) break;
             if ( j!=vcmp->ndref || a[j] ) continue;
             break;  // found
         }
 
         if ( vcmp->ndref>0 ) continue;
         for (j=0; j<-vcmp->ndref; j++)
-            if ( !b[j] || toupper(b[j])!=vcmp->dref[j] ) break;
+            if ( !b[j] || toupper_c(b[j])!=vcmp->dref[j] ) break;
         if ( j!=-vcmp->ndref || b[j] ) continue;
         break;  // found
     }