The regulatory region of the corticotropin-releasing hormone (CRH) is highly conserved across species and plays a crucial role in the response of the organism to stress. Release of CRH initiates a cascade of events leading to the release of cortisol and the regulation of inflammatory and immune events. In this report we describe polymorphisms in the 5' regulatory region of the CRH gene in humans. We studied the distribution of CRH alleles in three different African populations, in white UK Caucasoids, and in a Chinese population. In the African and UK populations we found three new polymorphisms which cosegregated, resulting in two alleles, A1 and A2. Gene frequencies for A1 and A2 were extremely divergent between the African and the UK populations. The African A1 frequency ranged from 0.27-0.3, while the UK Caucasoid frequency was 0.9. Compound alleles could be assigned by taking into account the previously described biallelic polymorphism at position 225 in the CRH promoter. The A2B1 compound allele is the commonest in contemporary African human populations (allele frequency range 0. 44-0.61) and was the only allele observed in a population of chimpanzees from Sierra Leone. Wright's F(ST )for the A2B1 allele over the four sampled populations was 0.612, a value exceeded in human populations only by loci which have apparently been subject to natural selection. Taken together, these findings support A2B1 as the ancestral allele and suggest that the CRH genomic region may have been subject to strong disruptive selection throughout human evolution.