In this issue of Blood, Schuetz et al analyze the immunologic and nonimmunologic outcomes in cohorts of severe combined immunodeficiency (SCID) patients with either RAG or ARTEMIS mutations following allogeneic hematopoietic stem cell transplantation (HSCT). The authors show that full immunologic recovery is more likely to be achieved if myeloablative conditioning is used; additionally, they show that in ARTEMIS patients, the use of alkylating chemotherapy agents is associated with a higher incidence of nonimmunologic complications. The challenge remains, especially in ARTEMIS deficiency, to achieve full immunologic recovery without long-term complications. The use of novel conditioning agents or the development of gene therapy strategies may help improve overall outcome for these patients.