The concept that antigens of a major histocompatibility locus (HL-A), the mixed leukocyte reaction, and the rejection of a graft are expressions of the same genetic region has been generally accepted. WE HAVE PRESENTED EXPERIMENTS THAT CHALLENGE THE ABOVE CONCEPT AND SUGGEST THAT THE REJECTION TIME OF SKIN AND ORGAN TRANSPLANTS IS DEPENDENT ON IMMUNIZATION AGAINST THE PRODUCTS OF TWO, AND POSSIBLY THREE, SEPARATE, BUT CLOSELY LINKED, GENETIC SYSTEMS: HL-A, mixed leukocyte reaction (MLR-S), and hypersensitivity delayed reaction (HDR). The findings presented and discussed here suggest that the HL-A antigens are not the primary factors involved in the cell-mediated component of allotransplantation, and that these antigens and phenotypes of the mixed leukocyte reaction can only be used as a guide in predicting the survival of allografts that are obtained from unrelated donors.