The evolution of highly polymorphic gene loci is following routes that cannot be extrapolated from the existing knowledge of single copy genes. In addition, interpreting the evolution of the most polymorphic loci in vertebrates requires a plethora of data from different taxa. We evaluate here the rules for the evolution of Major Histocompatibility Complex (MHC-)DRB genes recently established in humans and other primates on the basis of sequences from several artiodactyl species. MHC genes encode essential molecules for self/altered-self/non-self discrimination in the interaction of the organism with its environment. The necessity to effectively present various different antigens to immunocompetent cells causes positive selection pressure on the variability of these genes in the population. Artiodactyls represent the third mammalian order in which this phenomenon was evidenced independently. A further incentive to investigate also the surroundings of MHC-DRB loci was the presence of a particular repetitive sequence stretch in the vicinity of the polymorphic exon - in addition to the evolutionarily old alleles, ancient polymorphisms and the mechanisms for their generation and/or maintenance. Besides their utility for indirect gene diagnosis (MHC-DRB typing), the closely linked stretches of simple repetitive DNA in the neighborhood of the highly polymorphic MHC-DRB genes are also interesting remains of the evolutionary history. Evolutionary developmenl is different in genetically inert intron-ic DNA compared to the exonic counterparts, despite their close vicinity. The persistence of these simple repeats over nearly 100 million years in one location preserving the same basic motif structure is startling. Indirect evidence is weighed that biological meaning should be considered for these elements. The combined analysis of the polymorphic DRB genes and the (highly variable but persistent) simple repeat stretches deepen our understanding of the complexities within a unique genomic compartment encoding essential molecules for self/non-self dif-ferentiation in the interaction of the organism with its environment.