Allogeneic stem cell transplantation has proven an effective means of treatment for a variety of malignant and nonmalignant conditions. Stem cell transplantation has traditionally been preceded by the patient receiving high (myeloablative) doses of chemotherapy and total body irradiation, which have been associated with significant transplant-related morbidity and mortality. This finding has precluded some older or heavily pretreated patients from being offered stem cell transplantation and has made other populations, such as those with nonmalignant conditions, reluctant to consider this therapy. Preclinical studies demonstrated that engraftment of donor stem cells could be achieved with nonmyeloablative, but immunosuppressive, preparative regimens that are significantly less toxic. Preliminary clinical studies have shown that patients previously ineligible for allogeneic stem cell transplantation can frequently be safely transplanted and that an immune-mediated graft-versus-malignancy effect plays an important role in the antitumor efficacy of this treatment. The potential to use this nonmyeloablative approach in nonmalignant disorders in which regimen-related toxicity must be minimized is of particular interest in children.