Severe combined immunodeficiency (SCID) is caused by multiple genetic defects 1, 2, 3. The most common form of SCID, X-linked SCID (XSCID), results from mutations in IL2RG (ref. 4), which encodes the common cytokine receptor γ chain (γ c) that is shared by the IL-2, IL-4, IL-7, IL-9 and IL-15 receptors 1, 5, 6, 7, 8, 9, 10. In XSCID and SCID resulting from mutations in JAK3, which encodes a Janus family tyrosine kinase that couples to γ c (Refs 9, 12) and is required for γ c-dependent signalling, T-and natural killer (NK)-cells are decreased but B-cell numbers are normal 1, 2, 3, 13, 14 (T-B+ NK-SCID). Some SCID patients lack T cells but retain NK cells. Given diminished T-cell development in Il7-or Il7r-deficient mice 15, 16 and that Il7r-deficient mice have NK cells 17, we hypothesized that T–B+ NK+ SCID might result from defective IL-7 signalling, although apparent differences in the role of the IL-7/IL-7R pathway in humans and mice in T-cell and B-cell development have been suggested 1, 18. We now demonstrate that defective IL7R expression causes T–B+ NK+ SCID, indicating that the T-cell, but not the NK-cell, defect in XSCID results from inactivation of IL-7Rα signalling.