Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for treatment of otherwise incurable malignant and nonmalignant diseases, especially acute and chronic leukemias. Until recently, myeloablative regimens were considered mandatory for effective eradication of all malignant cells of host origin. Our preclinical and ongoing clinical studies indicated that eradication of host immunohematopoietic cells, including chemoradiotherapy-resistant leukemia, could be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion following induction of host-versus-graft transplantation tolerance mediated by engraftment of donor stem cells in the course of BMT. Thus, eradication of blood cancer cells, especially in patients with chronic myeloid leukemia and less frequently in patients with other hematologic malignancies, could be frequently accomplished despite complete resistance of such tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft-versus-leukemia (GVL) effects might be a useful tool for both treatment and prevention of relapse. Based on the aforementioned rationale, we speculated that the therapeutic benefit of BMT may be improved by using a safer conditioning as part of the transplant procedure, with the goal in mind to induce host-versus-graft tolerance to enable subsequent induction of GVL effects rather than attempt to eliminate host cells with hazardous myeloablative chemoradiotherapy. The latter hypothesis suggested that effective BMT procedure may be accomplished without lethal conditioning of the host, using a new well-tolerated nonmyeloablative regimen, thus possibly minimizing immediate and late side effects related to myeloablative procedures considered until recently mandatory for conditioning of BMT recipients. Recent clinical observations suggest that effective treatment of leukemia may be accomplished with a well-tolerated nonmyeloablative stem cell transplantation (NST) regimen, while avoiding immediate and late toxicity and minimizing procedure-related mortality. Taken together, our cumulative data suggest that high-dose chemotherapy and radiation therapy may be successively replaced by a more effective biological tool—alloreactive donor lymphocytes—thus setting the stage for innovative immunotherapeutic procedures for more selective and effective treatment of patients in need of BMT, including those resistant to conventional chemoradiotherapy.