Primary immunodeficiency diseases have been important targets of corrective gene transfer approaches since the very early days of gene therapy. The potential for selective survival advantage of gene-corrected cells over populations carrying the mutated, causative gene translates into the possibility of obtaining clinical meaningful results in patients with primary immunodeficiency diseases even if levels of gene transfer are low. This critical prospect has fueled the interest of researchers since the mid-1980s and has recently determined the success of a clinical trial of gene therapy for X-linked severe combined immunodeficiency.