The genomic organization and number of human HLA-DRB class II genes differs between haplotypes in the human population. In contrast, both HLA-DQ and -DP class II subregions are conserved. Understanding of the evolutionary relationship and age of HLA-DR haplotypes has been obtained by nucleotide sequence determination and phylogenetic analyses of intron sequences of all known DRB genes from different DR haplotypes. These analyses have indicated that the gene organization of some haplotypes has remained conserved for tens of millions of years and that novel haplotypes have originated during hominoid speciation. Thus, in the contemporary human population, both ancestral and species-specific DRB gene organizations are found. The plasticity of DR gene organization as well as the extensive allelic polymorphism of expressed DR-beta molecules are features which suggest that DR molecules are under distinct selective pressure compared to HLA-DQ and HLA-DP class II molecules. The extensive allelic polymorphism of HLA-DR transplantation antigens is exclusively provided by the beta-chain of these heterodimeric antigen presenting molecules. Most of this polymorphism appears to have been generated recently. Thus, evolutionary mechanisms involved in the preservation of ancestral gene organizations, selection against DR-alpha polymorphism, creation of DR-beta allelic polymorphism and generation of novel gene organizations are acting on the HLA-DR region simultaneously.