Pregnancy has been described as an immunological paradox because the maternal immune system accepts the fetus even though it expresses paternal antigens. Since placental tissues express maternal and paternal genes the immune system of the mother must tolerate the fetus to avoid its rejection. Placental expression of MHC-I proteins appears to play an important role in the regulation of the maternal immune system and protection of the conceptus from immune-mediated rejection. There are two types of MHC-I proteins. Classical MHC-I proteins, also called MHC-Ia, are highly polymorphic and are expressed by most nucleated cells. The non-classical proteins, also called MHC-Ib, are less polymorphic, are expressed by limited types of cells and are known to have immune modulatory effects in some species. In order to protect the fetus from maternal immune recognition most species down-regulate the expression of placental MHC-Ia proteins. Another commonly used mechanism is the upregulation of MHC-Ib expression by the trophoblast cells. The role of MHC-I proteins in the placenta has been studied in several animal species. This chapter will summarize the current literature on the expression of MHC-I proteins by the placenta of domestic and laboratory species. A lot remains to be learned about the types, function and regulation of expression of placental MHC-I proteins in domestic and laboratory animals