THE BEST, IF NOT ONLY, CURATIVE THERAPY for many patients with hematologic malignancies is allogeneic stem cell transplantation (SCT). It is now generally accepted that successful allogeneic SCT is dependent not only on the intensive conditioning therapy, but also on the anti-leukemic properties of the donor graft. This very important “graft-versus-leukemia” (GVL) effect is independent of the conditioning regimen and it is mediated, at least in part, by mature donor T cells contained in the stem cell graft. In fact, the rationale for some of the earliest trials of bone marrow transplantation were based on the use of allogeneic bone marrow as “adoptive immunotherapy” to destroy residual leukemia cells, and not just as a convenient source for hematopoietic “rescue” after myeloablative therapy (1). Unfortunately, despite many advances in conditioning regimens and supportive care, regimen-related toxicity, relapse, and graft-versus-host disease (GVHD) remain the major obstacles to successful allogeneic SCT. However, the ability to harness the GVL activity of allogeneic donor cells has provided the foundation for newer, safer approaches of allogeneic cell therapy (ACT) that begin to address problems such as relapse, conditioning regimen toxicity, and GVHD. In the past, the only curative therapy for relapsed leukemia after allogeneic SCT had been second SCT, but only at the expense of extensive morbidity, mortality, and very high relapse rates (2,3). Given conclusive preclinical data for important GVL activity and the indirect evidence for GVL reactions in the clinical setting, it was logical to test the potential for donor leukocyte infusions (DLI) to provide antileukemia activity for patients who relapse after allogeneic SCT. It has now been convincingly demonstrated that donor leukocytes can induce a direct GVL reaction in some patients with relapsed leukemia after allogeneic SCT and restore durable complete remissions without the need for any other conditioning therapy. This represents one of the best examples of successful adoptive immunotherapy and demonstrates that it is now possible to exploit the potent immunological properties of the human immune system for clinical benefit. The use of DLI for relapsed leukemia has led to trials using allogeneic adoptive immunotherapy as primary cancer therapy, either as primary DLI or with the use of nonmyeloablative conditioning and allogeneic SCT. Although many issues remain unsettled, the potential to harness the more general “graftversus-tumor” (GVT) activity of allogeneic donor cells may provide a new paradigm for allogeneic cell transplantation and the immunotherapy of cancer.