The efficacy of graft-vs.-leukemia induction to treat relapses after allogeneic progenitor cell transplant in a variety of hematologic malignancies suggest that it may be possible to use the graft versus leukemia as primary therapy for these malignancies without the need of myeloablative therapy. This type of strategy should be explored initially in patients considered ineligible for conventional myeloablative therapies either because of age or concurrent medical conditions. GVHD remains a major obstacle that needs to be overcome. Although a potentially lower level of inflammatory cytokines may be present after non-myeloablative therapies, fatal GVHD still occurs. Methods to diminish GVHD after allogeneic transplant include selective T-cell depletion (39-43) and transduction of donor T-cells with Herpes simplex virus thymidine kinase which renders these cells sensitive to ganciclovir treatment (see chapter 16). We and others have demonstrated that nonablative chemotherapy using fludarabine combinations is sufficiently immunosuppressive to allow engraftment of allogeneic blood progenitor cells. Patients could then receive graded doses of donor lymphocytes without rejection, to mediate GVL. Ideally, this therapy could be titrated to levels of residual malignant cells using sensitive detection techniques. This novel approach to therapy would reduce the toxicity of the transplant procedure, allow it to be administered more safely to debilitated patients and possibly extend the use of transplantation to older patients who are not presently eligible for BMT procedures. Other possible indications include treatment of non-malignant disorders and induction of tolerance for solid organ transplantation.