Two features distinguish the polymorphism of the major histocompatibility complex (MHC) loci from that of other loci: its high diversity and the large genetic distance between MHC alleles. More than 100 alleles exist in natural populations in the mouse at each of the functional class I and class II alleles, all alleles occurring at frequencies that cannot be explained by recurrent mutations. Some of the alleles differ by approximately 70 nucleotides in the coding region alone and some of the products of the allelic genes differ by more than 50 amino acids. It has generally been assumed that these differences accumulated after species inception. Here, we present evidence for an alternative explanation of the origin of MHC polymorphism: a large part of the MHC polymorphism pre-dates speciation and is passed on from species to species. We describe allelic differences that must have arisen before the separation of mice and rats from a common ancestor more than 10 million years ago.