In this review, we discuss the role of cytokines and their signaling pathways in immunodeficiency. We focus primarily on severe combined immunodeficiency (SCID) diseases as the most severe forms of primary immunodeficiencies, reviewing the different genetic causes of these diseases. We focus in particular on the range of forms of SCID that result from defects in cytokine-signaling pathways. The most common form of SCID, X-linked SCID, results from mutations in the common cytokine receptor gamma-chain, which is shared by the receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21, underscoring that X-linked SCID is indeed a disease of defective cytokine signaling. We also review the signaling pathways used by these cytokines and the phenotypes in humans and mice with defects in the cytokines or signaling pathways. We also briefly discuss other cytokines, such as interferon-gamma and IL-12, where mutations in the ligand or receptor or signaling components also cause clinical disease in humans.