Improvements in supportive care, antimicrobials, immunosuppressant therapy, and health care delivery have shifted the emphasis in hematopoietic stem cell transplantation toward raising cure rates and improving the quality of life in the years that follow transplantation. Many large centers have significantly reduced the morbidity of allogeneic transplantation by effecting a decrease in acute and chronic graft-versus-host disease. Extension of this modality through the use of unrelated donors, peripheral blood stem cell products, and HLA-mismatched family members has again introduced significant posttransplantation complications. Conversely, the posttransplantation morbidity of autologous transplantation is minimal, but the chances of remaining in long-term remission are still inferior to those afforded by allogeneic hematopoietic stem cell transplantation. One approach developed to reduce these long-term complications is referred to as "graft engineering." Through the use of successive clinical protocols, hematopoietic grafts and host immune properties can be manipulated in a stepwise fashion using several outcome parameters to judge efficacy. This report details one center's experiences with graft engineering over 12 consecutive years of clinical trials and speculates on future approaches that may supplant transplantation in the new millennium.