JAKs are non-receptor tyrosine kinases which couple to cytokine receptors, and are activated by cytokines. They regulate a spectrum of cellular functions downstream of activated cytokine receptors in the lympho-hematopoietic system. JAK kinases (JAK1, JAK2, JAK3, Tyk2) have a kinase domain and a second, pseudokinase domain which is not enzymatically active. The principal effectors of JAKs are the STATs (Signal Transducers and Activators of Transcription), which are direct activators of transcription, but JAKs also signal to the Ras-MAP Kinase pathway, and through Tec, to the PI3 Kinase pathway. Immunological stimuli, such as interferons and cytokines, induce recruitment of STAT transcription factors to cytokine receptor-associated JAK2. JAK2 then phosphorylates proximal STAT transcription factors, which subsequently dimerize and translocate to the nucleus where they bind DNA. The canonical JAK/Stat pathway is integral to maintaining a normal immune system by stimulating proliferation, differentiation, survival and host resistance to pathogens. Altering JAK/Stat signaling to reduce cytokine induced pro-inflammatory responses represents an attractive target for anti-inflammatory therapies. Within the JAK2 kinase domain, there is a region that has considerable sequence homology to the regulatory region of the insulin receptor. Among a variety of sites, Tyrosines 1007 and 1008 (Tyr1007/1008) are sites of trans- or autophosphorylation in vivo and in vitro kinase reactions. JAK2 is required for signaling through a different subset of cytokine receptors, while JAK1 is essential for signaling from the IL-2, IL-6 and interferon receptors. JAK3 is required for signaling through cytokine receptors which share a common gamma-chain.