Over the last 50 years, mouse models of bone marrow transplantation have provided the critical links between graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) pathophysiology and clinical practice. The initial insight from mouse models that GVHD and GVL were T cell dependent has long been confirmed clinically. More recent translations from mouse models have included the important role of inflammatory cytokines in GVHD. Newly developed concepts relating to the ability of antigen presenting cell (APC) and T cell subsets to mediate GVHD now promise significant clinical advances. The ability to use knockout and transgenic approaches to dissect mechanisms of GVHD and GVL mean that mouse systems will continue as the predominant preclinical platform. The basic transplant approach in these models, coupled with modern “real-time” immunologic imaging of GVHD and GVL is discussed.