In vertebrates, generation of the T- and B-cell repertoire relies on genomic rearrangement of T-cell receptor and immunoglobulin gene coding segments. This process, known as V(D)J recombination, is initiated by the lymphoid specific proteins Rag1 and Rag2. Both in humans and in animal models, mutations that abrogate expression of either the Rag1 or Rag2 proteins result in severe combined immune deficiency with a complete lack of circulating T and B cells due to an early block in lymphoid development. We have recently shown that mutations that impair, but do not completely abolish the function of Rag1 and Rag2 in humans result in Omenn syndrome, an enigmatic form of combined immune deficiency characterized by oligoclonal, activated T lymphocytes with a skewed Th2 profile.