Until further improvement in gene therapy is achieved, stem-cell transplantation is still the main option for cure of patients with primary immunodeficiency diseases. Performing the transplant in early infancy before severe infections and organ damage develop has the highest chance for success. The remarkable progress that has been achieved in understanding these disorders has made it possible to identify most of the genetic abnormalities. This enables an early transplant immediately after birth or even in utero. However, the optimal approach for stem-cell transplantation in children with immunodeficiency has yet to be determined. The non-myeloablative protocols increasingly used in recent years have the potential for immune reconstitution without considerable toxicity, but the experience is still limited. A better understanding of the specific immune dysfunction and the exact degree of residual immunity may enable the tailoring of the most appropriate conditioning regimen for each patient so that engraftment will be ensured with little morbidity.