The feline major histocompatibility complex (MHC) has been studied using molecular techniques as an approach to comparative genome organization of this important gene cluster. The MHC encodes two types of antigen- presenting molecules for T-cell receptors (class I and class II antigens) and controls immune responses to various pathogens and tumors. In the human MHC, over 100 genes have been identified in an approximately 4,000- kilobase region on the short arm of chromosome 6. The feline MHC region has about 20 class I genes, at least 2 alpha chain coding genes and 3 beta chain coding genes for class II molecules, and is located on a centromeric region of chromosome B2, which shows syntenic homology to human chromosome 6 and mouse chromosome 17. Sequence analyses of molecular clones of feline MHC class I and class II DR genes revealed that these feline molecules have structures similar to the human molecules and show highly polymorphic features in their antigen-binding sites. Several features in these MHC molecules, such as (i) extremely high degree of polymorphism, (ii) positive selection in favor of the polymorphism in the antigen-binding sites, (iii) a trans-species mode of polymorphism (common MHC polymorphism in separated species), and (iv) highly mosaic sequence structure, especially in class I genes, suggest that these MHC class I and class II molecules are under a strong balancing selection. This tends to retain many alleles increasing the immunological repertoire in populations. Detailed analyses for DRB class II alleles in cat populations, using the methods of polymerase chain reaction and single-stranded conformation polymorphism, and for the class I region using cosmid cloning and walking, are in progress.