MANY cytokines function through interaction with receptors of the cytokine receptor superfamily. Although lacking catalytic domains, cytokine receptors couple ligand binding to induction of protein tyrosine phosphorylation. Recent studies1-10 have shown that one or more of the Janus kinase family members (Jaks) associate with cytokine receptors and are tyrosine phosphorylated and activated following ligand binding. Here we describe a new Jak family kinase, Jak-3, and demonstrate that Jak-3, and to a lesser extent Jak-1, are tyrosine phosphorylated and Jak-3 is activated in the responses to interleukin-2 and interleukin-4 in T cells and myeloid cells. Jak-3 activation requires the serine-rich, membrane-proximal domain of the interleukin-2 receptor β-chain, but does not require the acidic domain that is required for association and activation of Src family kinases.