The goal of allogeneic (allo)-hematopoietic stem-cell transplantation (HSCT) in the treatment of hematologic malignancies is to harness the graft-versus-leukemia (GVL) effect, while minimizing the risk of graft-versus-host disease (GVHD). Allo-HSCT research has focused on the GVL target antigens and effector mechanisms, and on potential approaches to exploit GVL independently of GVHD. Donor lymphocyte infusion (DLI) achieves the most powerful anti-leukemic responses, and this approach is often used in combination with nonmyeloablative transplant regimens to optimize GVL and reduce GVHD. Serial, dose-escalating, and CD8⁺ T-cell-depleted DLI have been introduced into clinical practice, while other variants of DLI have so far been explored only in animal models. The role of naturally occurring regulatory T cells in transplantation tolerance is being increasingly acknowledged, and murine studies indicate the potential ability of T cells to regulate GVHD while maintaining GVL. Experimental and clinical studies have demonstrated the importance of host-type chimerism, particularly for antigen-presenting cells, in determining the occurrence of DLI-induced GVL. Murine studies could assist in the development of clinical strategies targeted at antigen-presenting cells. Clinical studies exploiting natural killer-cell-mediated antitumor reactivity in the context of killer inhibitory receptor-ligand-mismatched allo-HSCT have provided promising results.