The V2R genes are expressed in the mammalian vomeronasal organ, and their products are involved in detecting pheromones. Here, we describe the evolution of the V2R gene family. We have found that the human, chimpanzee, macaque, cow and dog V2R gene families have completely degenerated. Each now contains 9-20 pseudogenes but no intact V2R genes. By contrast, opossum has approximately 90 intact V2R genes that mostly arose by duplication after opossum and rodent lineages diverged. One V2R gene subfamily with unusual biology evolved atypically, showing limited expansion in rodents and persistence of a single, albeit sometimes dysfunctional, ortholog in all other species examined.