Despite significant progress in the past 20 years, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). T-cell depletion (TCD) of the donor graft offers the potential for prevention of GVHD without the morbidity associated with immunosuppressive drugs such as methotrexate and cyclosporine. Most early trials documented that TCD could substantially limit acute and chronic GVHD. However, this reduction in GVHD did not translate into improved overall survival because of unexpected high rates of graft failure, Epstein-Barr virus–associated lymphoproliferative disorders, and disease recurrence after TCD bone marrow transplantation. Despite the problems associated with TCD, great interest remains in developing and improving this technology, particularly for recipients of HLA-mismatched grafts. If advances in graft engineering can accomplish the goal of GVHD prevention without adversely affecting engraftment, immunocompetence, and antileukemic activity, then substantial improvements in overall transplant outcome can be realized.