Hematopoietic stem cell transplants (SCT) are used in the treatment of neoplastic diseases, in addition to congenital, autoimmune, and inflammatory disorders. Both autologous and allogeneic SCT are used, depending on donor availability and the type of disease being treated, resulting in different morbidity and outcomes. In both types of SCT, immune regulation via graft manipulation is being studied, although with highly different targeted outcomes. In general, autologous SCT have lower treatment-related morbidity and mortality, but a higher incidence of tumor relapse, and graft manipulation targets immune augmentation and/or the reduction of immune tolerance. In contrast, allogeneic SCT have a higher incidence of treatment-related morbidity and mortality and a significantly longer time of disease progression, and the targeted outcomes or graft manipulation focus on a reduction in graft versus host disease (GVHD). One source of the increased relapse rate and shorter overall survival (OS) following high dose chemotherapy (HDT) and autologous SCT is the immune tolerance that limits host response, both innate and antigen (Ag) specific, against the tumor. The immune tolerance that is observed is due in part to the tumor burden and prior cytotoxic therapy. Therefore, graft manipulation, as an adjuvant therapeutic approach in autologous SCT, is primarily focused on non-specific or specific immune augmentation using cytokines and vaccines. Recently, manipulation of the infused product as a form of cellular therapy has begun to also focus on approaches to reduce immune tolerance found in transplant patients, both prior to and following HDT and SCT. To this end, graft manipulation to reduce the presence of Fas Ligand (FasL)-expressing cells or interleukin (IL)10 and tumor growth factor (TGF)beta production has been proposed. In contrast to autologous transplantation, graft manipulation during allogeneic transplantation is used extensively. This includes limiting the infusion of T cells within the product or as a donor leukocyte infusion (DLI), resulting in a reduction in GVHD and the induction of long-term survivors. Indeed, allogeneic SCT provide the only curative therapy for patients with chronic myelogenous leukemia (CML), refractory acute leukemia, and myelodysplasia. The curative potential of allogeneic SCT is reduced, however, by the development of GVHD, a potentially lethal T-cell-mediated immune response targeting host tissues [Int. Arch. Allergy Immunol. 102 (1993) 309, J. Exp. Med. 183 (1996) 589]. The morbidity and mortality associated with GVHD limit this technology, resulting focus on those patients who have no alternative therapeutic options or who have advanced disease. Thus, allogeneic SCT provide one of the few statistically supported demonstrations of therapeutic efficacy by T cells (comparison of allogeneic to autologous transplantation). In contrast to autologous transplantation, control of GVHD following allogeneic SCT focuses on immune suppression and the induction of tolerance. Here too, graft manipulation is appropriate, and there are numerous studies of T-cell depletion to reduce GVHD, with or without the isolation and infusion of T cells as DLI. Additional strategies are examining the isolation and infusion of T cells with graft versus leukemia (GVL) activity to reduce GVHD and/or the infusion of genetically manipulated and/or selected cellular populations (monocytes or dendritic cells (DC)) to induce tolerance. Therefore, depending upon the type of transplant, the goals associated with graft manipulation can be radically different. In this review, we emphasize using graft manipulation to regulate immune tolerance and anergy in association with SCT. Although this paper focuses on hematopoietic SCT, it should be noted that these strategies are relevant to conditions other than neoplastic and congenital diseases, including solid organ transplants, and autoimmune and inflammatory diseases.