The domestic dog, Canis familiaris, is an excellent model species in which to study complex inherited diseases, having over 200 recognized breeds, each of which represents a closed gene pool. Overlapping canine genomic BAC clones were sequenced to obtain 711,521 bp of the canine classical and extended MHC class II regions. Analysis and annotation of this sequence reveals that it contains 45 loci, of which 29 are predicted to be functionally expressed. Comparison of the DLA class II sequence with those of the cat, human, and mouse highlights regions of syntenic conservation and species-specific gene rearrangement and duplication and gives an insight into the evolution of the DR region in the order Carnivora. Elucidation of functionally important dog class II genes and the identification of 23 microsatellite markers spanning this region will contribute significantly to the study of canine diseases that have an immune component.