Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for treatment of otherwise incurable malignant and non-malignant diseases. Until recently, autologous and allogeneic bone marrow or mobilized blood stem cells transplantation were used primarily to replace malignant, genetically abnormal or deficient immunohematopoietic compartment and therefore, highly toxic myeloablative regimen were considered mandatory for more effective eradication of all undesirable host-derived hematopoietic elements. Our preclinical and ongoing clinical studies indicated that much more effective eradication of host immunohematopoietic system cells could be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion following BMT. Thus, eradication of blood cancer cells, especially in patients with CML 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 eradication of otherwise resistant tumor cells of host origin. Based on the cumulative clinical experience and experimental data in animal models of human diseases it appears that induction of host versus graft tolerance as step one, may allow durable engraftment of donor immunocompetent lymphocytes, which may be used for induction of effective biologic warfare against host-type immunohematopoietic cells that need to be replaced, malignant, genetically abnormal or self-reactive alike. 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, possibly graft versus tumor or even graft versus autoimmunity 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 new well tolerated non-myeloablative regimen, thus possibly minimizing immediate and late side effects related to myeloablative procedures considered until recently mandatory for conditioning of BMT recipients. Recent clinical data that will be presented suggests that effective BMT procedures may be accomplished with well-tolerated non-myeloablative stem cell transplantation (NST) regimen, with no major toxicity. Thus, new NST approaches may offer the feasibility of safer BMT procedure for a large spectrum of clinical indications in children and elderly individuals without lower or upper age limit, while minimizing procedure-related toxicity and mortality. Taken together, our cumulative data suggest that high dose chemotherapy and radiation therapy may be successively replaced by a more effective biologic tool, alloreactive donor lymphocytes, thus setting the stage for innovative therapeutic procedures for safer and more effective treatment of patients in need of BMT.