Allogeneic transplantation is routinely employed as curative therapy for patients with hematologic malignancies and, increasingly, for a variety of non-malignant diseases. Overcoming the barrier of alloimmunity is fundamental to the success of allogeneic transplantation. Thus, the development of potent immunosuppressive medications was the key event leading to the routine use of transplantation for the treatment of hematologic malignancies. Methotrexate was the first widely used immunosuppressive agent, and the development of cyclosporine A in the early 1970s represented a major breakthrough in immunosuppression. Methotrexate acts as an antiproliferative agent, preventing cell cycling and division of activated T cells, while cyclosporine A acts by preventing T-cell activation and upregulation in response to inflammatory cytokines and paracrine T-cell signaling. Used individually, each provides some degree of protection against lethal acute graft-versus-host disease (GvHD), although single-agent methotrexate is associated with very modest success. Cyclosporine was noted to be more potent as post-transplant monotherapy when compared with methotrexate, leading ultimately to the clinical trial described below.