Acute graft-versus-host disease (GVHD) remains a major obstacle to successful allogeneic hematopoietic stem cell transplantation (HSCT). The ability to prevent GVHD--the application of successful prophylaxis--is crucial as treatment when prophylaxis fails or remains suboptimal. A calcineurin inhibitor in combination with methotrexate is still the mainstream regimen for prophylaxis of GVHD. Despite a steady increase in the repertoire of available drugs, corticosteroids remain the first-line therapy for patients who fail prevention and develop GVHD. Pan T-cell depletion studies suggest that success in prophylaxis and treatment of GVHD will depend on whether GVHD can be prevented without losing anti-malignancy and anti-infectious effects. Better understanding of the allogeneic response that is responsible for GVHD will facilitate the development of such an approach.