Despite progress in allogeneic hematopoietic stem cell transplantation during the past three decades, graft-versus-host disease (GVHD) still contributes substantially to transplant-related morbidity and mortality. Although current strategies to prevent or treat this complication remain unsatisfactory, new insights into its pathophysiology have yielded novel targets for GVHD prophylaxis and therapy. Regulating GVHD without sacrificing beneficial graft-versus-tumor reactivity and immune competence continues to be an elusive goal. Many promising new interventions have undergone limited clinical evaluation, but controlled studies are needed to define their roles more clearly. Refinements in clinical grading systems and prognostic indices will facilitate the study of new strategies in GVHD prevention and treatment.