Allogeneic bone marrow transplantation (BMT) or blood stem cell transplantation represents an important therapeutic tool for the treatment of otherwise incurable malignant and nonmalignant diseases. Until recently, autologous and allogeneic BMT or mobilized blood stem cell transplantation was used primarily to replace a malignant, genetically abnormal, or deficient immunohematopoietic compartment, and therefore highly toxic myeloablative regimens were considered mandatory for eradication of all undesirable host-derived hematopoietic elements. Our preclinical and ongoing clinical studies have indicated that 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 chronic myelogenous leukemia and less frequently in patients with other hematologic malignancies, can frequently be achieved despite complete resistance of such tumor cells to the maximum tolerated doses of chemoradiotherapy. Our cumulative experience suggests that graft vs 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 vs graft tolerance as the first step may allow durable engraftment of immunocompetent donor lymphocytes, which may be used for induction of effective biologic warfare against host-type immunohematopoietic cells that need to be replaced, whether they are malignant, genetically abnormal, or self-reactive. Based on this rationale, we speculate that the therapeutic benefit of BMT may be increased by using safer conditioning as part of the transplantation procedure, with the goal of inducing host vs graft tolerance to enable subsequent induction of GVL, possibly graft vs tumor, or even graft vs autoimmunity effects, rather than attempting to eliminate host cells with hazardous myeloablative chemoradiotherapy. Our hypothesis suggests that effective BMT procedures might be accomplished without lethal conditioning of the host, using new, well-tolerated nonmyeloablative regimens, possibly minimizing immediate and late side effects related to myeloablative procedures. Recent clinical data suggest that effective BMT procedures may be accomplished with nonmyeloablative stem cell transplantation (NST) regimens, with no major toxicity. Thus new NST approaches may make BMT procedures safer for a spectrum of clinical indications in children and elderly individuals without lower or upper age limits, while minimizing procedure-related toxicity and mortality. Our cumulative data suggest that high-dose chemotherapy and radiation therapy may be successively replaced by more effective alloreactive donor lymphocytes, thus setting the stage for innovative therapeutic procedures with safer and more effective treatment of patients requiring BMT.