In each species sufficently studied, a single genetic region, the major histocompatibility complex (MHC), controls the strong transplantation antigens. Recent evidence suggests that the genetic control of differences important in allograft phenomenon is more complex than previously realized. In addition to the two loci, alleles of which control serologically defined (SD) antigens, there are other loci the phenotypic products of which lead to T-lymphocyte activation in mixed leukocyte culture. These latter loci have been referred to as LD (or lymphocyte defined). There appears to be a physiologic interaction between these two loci in that the LD differences seem to be important in the initial recognitive phases of the allograft reaction; the SD differences (or products of genes very closely linked to those determining the SD antigens) are important as a target for cytotoxicity as studied by the cell-mediated lympholysis test.