A brief historic review of bone-marrow transplantation, human leukocyte antigen matching, pretransplant conditioning, and the use of peripheral blood stem cells in hematopoietic cell transplantation (HCT) is presented. Graft-versus-host disease (GVHD) is one of the primary challenges to successful HCT. GVHD, its clinical impact and traditional prophylactic therapies, as well as recent advances in GVHD prevention, are discussed.