Conventional allogeneic stem cell transplantation is a valuable approach to therapy for many hematologic malignancies. However, high-dose conditioning regimens designed both to control the malignancy and to prevent graft rejection are associated with a high incidence of acute and long-term side-effects. This has largely precluded the use of allografting for patients older than 55 years or for younger patients with certain pre-existing organ damage. In order to manage the side-effects, transplants have traditionally been delivered in highly specialized hospital wards or intensive care settings. Thus, an important goal is to develop safer allografting procedures that can be extended to older patients or patients with pre-existing organ dysfunction who are currently excluded from consideration for transplant. Recent observations have shown that donor lymphocyte infusions (DLI) can eradicate some malignancies that relapse after conventional allografting. These observations confirmed earlier evidence in favor of a graft-versus-leukemia effect based on the association of graft-versus-host disease (GVHD) with a lower likelihood of relapse of malignancy after allografting. Given the potential efficacy of DLI as the sole modality for eradication of malignancy, new strategies for allografting can incorporate the concept of less intensive conditioning therapy which is given with the sole aim of facilitating allogeneic engraftment. Recent pre-clinical studies in a canine model have shown that conditioning regimens for allografting can be markedly reduced in intensity yet still achieve the goal of engraftment. This review briefly summarizes the initial translational clinical studies, using a minimally myelosuppressive-conditioning regimen based on low dose total body irradiation (TBI) or fludarabine alone or in combination with other drugs followed by a short course of immunosuppression with post-grafting cyclosporine and methotrexate or mycophenolate mofetil.