The nature of polymorphism and molecular sequence variation in the genes of the human major histocompatibility complex (MHC) provides strong support for the idea that these genes are under selection. With the understanding that selection shapes MHC variation new questions have become the focus of study. What is the mode of selection that accounts for MHC polymorphism? Is variation maintained by pathogen pressure or by reproductive mechanisms? Discerning between these requires drawing on information from studies on association between HLA genes and infectious diseases, reproductive success and mating preferences relative to HLA genotypes, and theoretical studies that compare the outcomes of different selection regimes. The pattern that has emerged suggests that several types of selection are plausible for the maintenance of HLA polymorphism.