There are numerous inherited immunodeficiencies characterized by either defects in T, B lymphocytes, phagocytic cells or the complement system. About 20 genes involved in inherited immunodeficiencies have now been identified. This opens theorically the possibility to consider gene therapy for the most severe of the diseases. A logical approach consists in attempting gene transfer into hematopoietic stem cells in order to achieve a definitive cure. However, the presently available vectors, i.e. retroviruses induce only stable gene integration and possibly expression into cycling cells while most stem cells are in G0/G1. This precludes at this time efficient gene therapy for many inherited immunodeficiencies. Nevertheless in instances, where there is an early block in cell differentiation like in adenosine desaminase deficiency (ADA) or X-L severe combined immunodeficiency (IL2 R gamma deficiencies), a selective advantage could be provided to the few transduced stem cells enabling progressive lymphocyte differentiation. This hypothesis sets the basis for the ongoing clinical studies in patients with ADA deficiency and will be assessed in available animal model of XL SCID.