The MHC is of overwhelming importance in determining the fate of an allograft. Over the past 10 years, our understanding of the serology of this locus, its role in cellular immunity, its biochemistry, and most recently, its molecular biology has increased enormously. Genes for all the known loci, both Class I and Class II, have been cloned and sequenced, and their evolution and function are therefore now more amenable to investigation at the molecular level. Concomitantly, an understanding of the different populations of immune cells involved in the recognition of the antigens encoded by these loci has permitted a more precise immunologic description of the rejection response. It is now clear that recognition of both Class I and Class II allogeneic differences by both helper and cytotoxic T cells has an important role in graft rejection. The goal of transplantation biologists is to take advantage of this increased understanding in order to design new techniques for specifically modifying the immune response to MHC antigens and achieving specific tolerance. Some exciting approaches are already being studied, including specific modifications of both the antigen and the receptor arms of the immune response. It is hoped that these approaches will have new clinical applications in the near future.