Medawar and Billingham in their classic experiments described three prerequisites for the development of graft-versus-host disease (GVHD): first, the presence of immunocompetent cells in the donor inoculum; second, the inability of the recipient to reject the donor cells; and third, a histocompatibility difference between the donor and recipient. These experiments are the basis for all later hypotheses related to the pathogenesis of GVHD. Recently, de Gast and colleagues reviewed the role of environmental antigens in the pathogenesis of GVHD and suggested that immunological responses to environmental antigens by the transplanted donor cells might contribute to an increased donor anti-recipient response. An area not addressed in that review was the potential role of autoreactivity in GVHD. In this short article, Robertson Parkman highlights the role of autoreactivity and autoantigens in the pathogenesis of both acute and chronic GVHD in histocompatible bone marrow transplantation.