As mice are often used to model human major histocompatibility complex (MHC)-associated diseases, it is important to understand how their MHC regions differ at the DNA level. The sequencing of the mouse MHC (H2 region) has enabled a detailed map of this region to be assembled for comparison with the human MHC. Here, Richard Allcock and colleagues outline the similarities between the human and mouse MHC regions and discuss notable differences that might affect disease models.