Graft-versus-host disease (GVHD) is a complex condition that can occur after allogeneic bone marrow transplantation and remains a significant cause of morbidity. GVHD occurs when donor immunocompetent T cells react to and attack the genetically disparate host. The etiology of GVHD is complex, with numerous variables affecting its incidence and severity. Recent work has focused upon blunting the initial interactions between the donor T cell and the host. Because GVHD is linked with the beneficial graft-versus-tumor (GVT) effect that occurs after allogenic bone marrow transplantation, previous attempts to circumvent GVHD (i.e. by depletion of T cells from the donor graft) also resulted in increased relapse rates from the original tumor. The ideal scenario involves the tolerization or anergy of the donor T cell that attacks the host while allowing donor cells to mediate GVT effects. Recent work has attempted to address several pivotal features of GVHD: the variables that affect its induction and severity; the effector mechanisms; and whether GVHD can be suppressed yet GVT effects be maintained. Questions about these features need answers to enable us to design successful approaches for intervention.