Cytokine pathways are essential for the differentiation and function of lymphoid cells. The major T-cell growth factor is IL-2, which is produced by subsets of T lymphocytes in response to antigenic stimulation. The IL-2 receptor is expressed by T cells after antigenic stimulation, and when engaged by IL-2 induces proliferation, differentiation, and protection from apoptosis. Rare patients with severe combined immune deficiency (SCID) have been found to have mature T lymphocytes that do not produce IL-2, although no genetic abnormality has yet been defined for these patients. The fact that these patients and IL-2 knockout mice have the ability to generate mature T lymphocytes indicates that IL-2 is the major growth factor for mature T lymphocytes but not for immature thymocytes. X-linked SCID, the most common form of SCID, has a phenotype of thymic hypoplasia, peripheral T lymphopenia, the presence of B lymphocytes that do not undergo normal class switching, and usually the absence of natural killer (NK) cells. X-SCID is caused by mutations of a receptor subunit, which was originally described as the IL-2Rgamma. The phenotypic differences between X-SCID and IL-2-deficient SCID suggests that the IL-2Rgamma chain might be a component of other receptors needed for thymic development, B cell class-switching, and NK development. The IL-2Rgamma is now known to be a shared subunit between the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors, which explains the complex X-SCID phenotype. Because of this shared usage, the IL-2Rgamma is known as the common gamma chain (gamma c). Each ligand induces dimerization of gamma c with the ligand-specific receptor subunit, eg, the IL-2Rbeta, resulting in signal transduction through the JAK-STAT (signal transducers and activators of transcription) pathway. The JAK3 tyrosine kinase is constitutively associated with the gamma c and is necessary for signaling through the gamma c-containing receptors. Deficiency of JAK3 gives rise to a SCID phenotype that closely resembles that of X-SCID, but is autosomally recessive in inheritance. It is likely that other specific immune deficiencies of the cytokine pathways exist, eg, IL-7Ralpha-deficient SCID. T cells with wild-type gamma c and JAK3 proteins have a profound selective advantage over cells that contain mutant proteins. The selective advantage allows these patients to be treated by bone marrow transplantation (BMT) without ablative chemotherapy, and is the reason that these forms of SCID are potential targets for early gene therapy efforts.