Inherited defects in T lymphocyte development (severe combined immunodeficiencies-SCID) are considered the best available models to assess the effectiveness of gene therapy. Retroviral vectors have been successfully used ex vivo to transduce hematopoietic precursors from patients with two forms of SCID, namely X-linked SCID and ADA deficiency. Fifteen out of 16 patients with XL-SCID and 4 out of 4 patients with ADA deficiency have benefited from gene therapy. Correction of the immunodeficiency has been maintained now for 6 years in the first patients to be treated. These results provide clear-cut proof of the principle of gene therapy in relevant clinical models. However, three patients with XL-SCID have developed a severe complication after gene therapy, consisting of leukemia-like clonal lymphocyte proliferation. One of the three patients has died from this complication. It is due to provirus insertion within or close to proto-oncogenes, and to the enhancer activity of the viral LTR on targeted proto-oncogenes. Vector modifications, based mostly on inactivating the enhancer activity of the LTR, should preserve efficacy while improving safety.