NST is becoming a widely accepted method for allogeneic HSCT. Much experience has been gained, and the biology, indications and limitations are becoming clearer. Nonmyeloablative conditioning allows consistent engraftment of allografts from matched related, unrelated, and even partially matched donors. NST has been able to reduce the toxicity of allogeneic HSCT. The better immediate outcome produces better overall DFS. NST was feasible in elderly patients with almost no upper age limit, and in patients with organ dysfunction or other comorbidities precluding standard ablative conditioning. NST has also reduced the regimen-related toxicity of allogeneic HSCT in high-risk setting such as HSCT in heavily pretreated patients or following failure of a prior transplant procedure and in the unrelated setting. NST is rapidly becoming the treatment of choice in these indications where toxicity of standard ablative therapy is unacceptable. In certain malignancies such as in NHL, Hodgkin's disease and multiple myeloma, standard ablative NST has been reported to result in exceptionally high treatment related mortality, and NST is being investigated as a more reasonable alternative. NST may reduce the toxicity of the procedure even in younger patients who are eligible for ablative HSCT as well, however the long-term impact on patient outcome in this group is not yet established, and NST merits further investigation in prospective comparative trials. As described above, the known susceptibility of the underlying malignancy to GVT, the response to prior chemotherapy and bulk of residual disease, and the type of donor are other factors to consider when considering NST, and when selecting a regimen. The optimal preparative regimen needs to be defined. Ultimately less chemotherapy will be used and more specific immune-modulation, rather than intense nonspecific immunosuppression, will be used to achieve HVG tolerance. Preliminary animal models using costimulation blockade for specific induction of tolerance are promising steps towards achievement of this goal. Although much progress has been achieved with consistent achievement of engraftment with NST, GVHD and disease recurrence remain major obstacles to successful treatment. Existing clinical data suggest that NST does limit the incidence and severity of GVHD. Limitation of regimen-related toxicity, and bilateral transplantation tolerance afforded by mixed chimerism, are believed to have a major role in limiting GVHD. However GVHD remains the primary cause of treatment-related mortality. The development of techniques to separate GVHD and GVL are essential for further improvement of NST outcome. Better understanding of the biology and targets of GVHD and GVL may allow the elimination of alloreactive T-cells responsible for GVHD from the graft while retaining T-cells with GVL and infection control potential. Recurrence of the underlying malignancy is a major complication when NST is attempted in patients with chemo-refractory diseases and with high tumor bulk. Reduced toxicity regimens such as the FB/ATG regimen have been somewhat more successful in controlling disease progression until a potent GVT effect is established. However novel approaches are urgently required. NST serves as a platform for cellular immunotherapy. Judicious use of pre-emptive DLI needs to be explored. DLI may be amplified by activation of donor lymphocytes with IL-2 or in vivo administration of IL-2. Identification of tumor antigens will lead the way to ex-vivo generation and expansion of tumor specific cytotoxic T-lymphocytes to be used as potent immunotherapy without the hazards of GVHD. Allogeneic transplantation is rapidly changing from administration of supralethal doses of chemotherapy and radiation, trying to physically eliminate the 'last tumor cell', to the more subtle and tolerated sophisticated immunotherapy. This effort will focus on specific induction of HVG tolerance followed by induction of tumor-specific GVT effect to cure the underlying malignancy.