Abstract The last 6 decades have seen major advances in the understanding of immunologic diseases, driven by preclinical animal models. Indeed, bone marrow transplantation (BMT) has its genesis in rodent models dating back to the 1950s. Allogeneic BMT and its major complication, graft-versus-host disease (GVHD), represent a paradigm for the translation of preclinical concepts into clinical practice. The appreciation that GVHD can be thought of as a stepwise escalation in immune activation characterized by eventual massive target tissue apoptosis has allowed the design of rational approaches to better manage patients. Here, we describe the pathophysiology of GVHD as defined in preclinical models, focusing on the successes and failures of this research to instruct and translate clinical practice. We also provide a commentary on the limitations of these models so that they may be better appreciated and addressed in future studies. Notable preclinical successes include the definition of modern immune suppression, reductions in conditioning intensity, posttransplant cyclophosphamide, and the promotion of regulatory T-cell reconstitution. New strategies including naïve T-cell depletion, focused cytokine and chemokine inhibition, and the blockade of costimulation now also appear highly promising and very likely to translate into patients in the near future.