A variety of important cellular functions are regulated by cytokines. The Jak-STAT pathway is one of the important signaling pathways downstream of cytokine receptors. Following binding of a ligand to its cognate receptor, receptor-associated Jaks are activated. STAT proteins are then in turn activated by tyrosine phosphorylation by Jak kinases, allowing their dimerization and subsequent translocation into the nucleus, where they modulate expression of target genes. Indispensable functions of Jaks and STATs in cytokine signaling in vivo have been revealed through knockout mouse studies. Moreover, the recent discovery of the CIS/SOCS/JAB/SSI family of inhibitors has contributed to understanding how this pathway is negatively regulated.