Infectious agents select for host immune responses that destroy infectious nonself yet maintain tolerance to self. Here we propose that retroviruses and other host-antigen associated pathogens (HAAPs) select for the genetic, biochemical, and cell biological properties of alloimmunity, also known as the histocompatibility or tissue rejection response. This hypothesis predicts the major observations regarding histocompatibility responses, including: (i) their existence in animals as diverse as sponges and humans; (ii) extreme polymorphism and balanced allele frequencies at histocompatibility loci, including the human MHC and blood group loci; (iii) the frequency dependent selection of histocompatibility alleles; (iv) the ancient age of many alloantigenic polymorphisms; (v) the high ratio of nonsynonymous mutations to synonymous mutations at histocompatibility loci; (vi) disassortative mating based on MHC alleles; (vii) the inability to explain the existence and continuing selection of histocompatibility alleles by other more conventional biochemical and genetic paradigms; and (viii) the susceptibility of HAAPs, particularly retroviruses such as HIV (human immunodeficiency virus), to histocompatibility reactions. In addition, the hypothesis that HAAPs select the forms and molecules of alloimmunity offers simple explanations for the evolution of histocompatibility systems over time, the initial selection of hypervariable immune mechanisms, and the genesis of adaptive immunity.