Hematopoietic stem cell transplantation (HCT) may offer the only curative therapy for certain life-threatening immune deficiency disorders. Conventional HCT poses a risk to patients for severe morbidity, mortality, and late sequelae resulting from myeloablative preparative regimens. This review summarizes the development of nonmyeloablative regimens that have the potential to reduce both short- and long-term risks of HCT. Results of NM-HCT in a small number of patients indicate that this procedure may play an important role in treatment of life-threatening immune deficiencies.