The human histocompatibility system (HLA) is a linked complex of genes on human chromosomes 6. Many of the loci in this region are highly polymorphic. This endows the system with unique differentiating powers, both in terms of the population genetics of the reconstruction of evolutionary trees to assess biological divergences (or affinities) in human populations, and in terms of detecting the genetic component of the many diseases which show an association with certain variants (alleles) of the HLA system. Different racial groups often exhibit different HLA disease associations; that is, a different allele is associated with the disease in different populations, although in some cases the same allele is associated with the disease in all populations. The classical example of this latter situation is the association of B27 with ankylosing spondylitis. This disease will be used as an example to illustrate how population observations allow inferences to be made regarding the evolutionary histories of the HLA-associated diseases, as well as the genetic mechanisms of the diseases.