The discovery of the human MHC in 1967 launched the field of organ and tissue transplantation. More than 800,000 such transplants have been performed during this time. Although matching of donor and recipient for MHC antigens was shown to be of great importance and continues to be so, the development of pharmacologic agents and antilymphocyte antibodies that interfere with the process of graft rejection has had a crucial role in the success of organ transplantation during the past 2 decades. Enormous progress has been made in understanding the immunologic mechanisms of graft rejection and of graft-versus-host disease. The roles of antibodies, antigen-presenting cells, helper and cytotoxic T cells, immune cell surface molecules, and signaling mechanisms and the cytokines they release have been clarified. This understanding is leading to the development of newer immunosuppressive agents targeting various components of the rejection process. Combinations of these agents work synergistically, leading to lower doses and reduced toxicity. Similarly, the development of effective T-cell depletion techniques has been of great importance for bone marrow transplantation when an HLA-identical sibling is not available. The major obstacle to the performance of solid organ transplantation currently is the shortage of donor organs.