Nonmyeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT) have been developed over the past few years as important alternatives to conventional myeloablative conditioning regimens for older or medically unfit patients with hematologic malignancies, as well as for patients with certain nonmalignant hematologic diseases or renal cell cancer. This review summarizes the biological background, current clinical applications, and indications for this novel treatment approach for treating hematologic malignancies. Historically, allogeneic HSCT has been based on the use of cytotoxic and myeloablative chemotherapy and radiotherapy conditioning regimens that are intended both to eradicate malignancy and to eliminate host hematopoiesis and immune cells. Such a regimen was followed by the infusion of histocompatible donor marrow or peripheral blood stem cells to rescue hematopoiesis. For older patients or for those who had previously been treated with intensive chemotherapy or radiotherapy, the toxicity of myeloablative conditioning was prohibitive. Although most hematologic malignancies occur in older patients, these patients had not been previously eligible for the potentially curative therapy offered by allogeneic HSCT. Based in large part on preclinical studies with the dog model of HSCT and on an improved understanding of the mechanisms for controlling immune modulation, successful development of nonmyeloablative conditioning regimens for clinical use has occurred. Clear evidence of a therapeutic graft-versus-tumor effect mediated by allogeneic T-cells prompted an exploration for HSCT regimens that rely solely on nonmyeloablative immunosuppression to facilitate allogeneic engraftment. In lieu of intensive chemoradiotherapy before transplantation, engrafted donor T-cells are used to accomplish the task of eradicating the host's malignant cells. We review the updated results of an ongoing multicenter study to investigate the safety and efficacy of nonmyeloablative HSCT using a regimen of 2 Gy total body irradiation in patients with advanced hematologic malignancies who were ineligible for conventional myeloablative conditioning. In addition, we review the results of reduced-intensity HSCT trials from other transplantation centers.