The mammalian JAK family has four members: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). The connection between Jaks and cytokine signaling was first revealed when a screen for genes involved in interferon type I (IFN-1) signaling identified Tyk2 as an essential element, which is activated by an array of cytokine receptors. Tyk2 has broader and profound functions in humans than previously appreciated on the basis of analysis of murine models, which indicate that Tyk2 functions primarily in IL-12 and type I-IFN signaling. Tyk2 deficiency has more dramatic effects in human cells than in mouse cells. However, in addition to IFN-α and -β and IL-12 signaling, Tyk2 has major effects on the transduction of IL-23, IL-10, and IL-6 signals. Since, IL-6 signals through the gp-130 receptor-chain that is common to a large family of cytokines, including IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF, Tyk2 might also affect signaling through these cytokines. Recently, it has been recognized that IL-12 and IL-23 share ligand and receptor subunits that activate Tyk2. IL-10 is a critical anti-inflammatory cytokine, and IL-10−/− mice suffer from fatal, systemic autoimmune disease.