The focus of our research for the past decade has been the development of treatment strategies to modulate the immune system of patients with cancer. These efforts are based on studies of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies. Although allogeneic transplantation can cure a proportion of these individuals, success is limited by transplant-related complications such as graft-versus-host disease (GVHD). It has long been recognized that T lymphocytes from the donor marrow play a pivotal role in the pathogenesis of GVHD. In patients undergoing HSCT, depleting donor marrow T cells with an antibody to a T cell surface structure results in a dramatic decrease in the incidence of GVHD. This approach also eliminates the need for immune-suppressive medications. These agents can be toxic, causing organ damage and increasing susceptibility to infection. Recently we have explored strategies to selectively infuse CD8+ depleted lymphocytes in hopes of prompting graft-versus-leukemia (GVL) activity without producing GVHD. We validated this strategy in a randomized trial of CD8-depleted donor lymphocyte infusions after T cell-depleted allotransplantation, and are now conducting further trials on CD8 depletion. While T cell depletion reduces GVHD, its effect on immune reactivity may lead to an increased risk of relapse of certain leukemias after transplantation. Preserving and restoring this GVL activity without compromising safety is a major thrust of our clinical and laboratory research.