Major Histocompatibility Complex (MHC) genes play a key role in immune response to infectious diseases, immunosurveillance, and self/nonself recognition. Matching MHC alleles is critical for organ transplantation, while changes in the MHC profile of tumour cells allow effective evasion of the immune response. Two unique cancers have exploited these features to become transmissible. In this review I discuss the functional role of MHC molecules in the emergence and evolution of Devil Facial Tumour Disease (DFTD) and Canine Transmissible Venereal Tumour (CTVT). High levels of genetic diversity at MHC genes play a critical role in protecting populations of vertebrate species from contagious cancer. However, species that have undergone genetic bottlenecks and have lost diversity at MHC genes are at risk of transmissible tumours. Moreover, evolution and selection for tumour variants capable of evading the immune response allow contagious cancers to cross MHC barriers. Transmissible cancers are rare but they can provide unique insights into the genetics and immunology of tumours and organ transplants.