Omenn syndrome (OS) is a peculiar, autosomal recessive severe combined immunodeficiency (SCID) associated with early-onset, generalized, exudative erythrodermia; lymphoadenopathy; hepato- and splenomegaly; hypereosinophilia; elevated serum IgE; and normal to high activated, yet non-functional, oligoclonal T cells. Recent investigations have shown that the primum movens of all these puzzling features lies in a defect of the lymphoid-specific V(D)J recombination process. Abnormalities in both alleles of either Rag-1 or -2 genes are found in all OS patients. At variance with T B- SCID, whose Rag mutations represent null alleles, OS mutations maintain a residual recombination activity, allowing limited T-cell receptor gene rearrangements to occur in the thymus. The gene rearrangements are subsequently expanded in the periphery after environmental antigen exposure. Missense mutations detected in OS have been examined in a number of biochemical assays and have contributed to dissect the various functional domains of both Rag-1 and Rag-2 proteins. The examination of a set of mutations occurring in the Rag-1 N-terminal portion has demonstrated that this region plays a fundamental role in vivo. The elucidation of the molecular basis of OS has allowed us to perform early prenatal diagnosis and could be the basis for trials of in utero bone marrow transplantation or gene therapy approaches.