Hematopoietic stem cell transplantation has evolved as a central treatment modality in the management of different hematologic malignancies. Despite adequate posttransplantation immunosuppressive therapy, acute graft‐versus‐host disease (GVHD) remains a major cause of morbidity and mortality in the hematopoietic stem cell transplantation setting, even in patients who receive human leukemic antigen (HLA) identical sibling grafts. Up to 30% of the recipients of stem cells or bone marrow transplantation from HLA‐identical related donors and most patients who receive cells from other sources (matched‐unrelated, non‐HLA‐identical siblings, cord blood) will develop > Grade 2 acute GVHD despite immunosuppressive prophylaxis. Thus, GVHD continues to be a major limitation to successful hematopoietic stem cell transplantation. In this review, the authors summarize the most current knowledge on the pathophysiology, clinical manifestations, and management of this potentially life‐threatening transplantation complication. Cancer 2004. © 2004 American Cancer Society.