Cytokines play pivotal roles in immunity and inflammation, and targeting cytokines and their receptors is an effective means of treating such disorders. Type I and II cytokine receptors associate with Janus family kinases (JAKs; EC 2.7.10.2) to effect intracellular signaling. The JAK family in mammals consists of 4 members: JAK1, JAK2, JAK3 and TYK2. The unique structure of the JAK kinases clearly distinguishes them from other members of the protein tyrosine kinase family. The most intriguing feature of these proteins is the presence of two JAK-homology domains (JH1 and JH2), with extensive homology to the tyrosine kinase domains. A second interesting feature is the absence of any Src-homology domains SH2 or SH3. Instead, these proteins encode a group of well-conserved domains termed as JAK homology (JH1-JH7) domains that follow a non-conserved amino terminus of about 30-50 amino acids. Of the dual kinase domains identified, only the JH1 domain appears to be functional. JAK activation occurs upon ligand-mediated receptor multimerization. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates, STATs (latent transcription factors that reside in the cytoplasm until activated).