Src homology 2 (SH2) domains interact in a highly specific manner with phosphorylated tyrosine residues on other signaling molecules. Protein tyrosine kinases (PTK) frequently contain SH2 domains, which often control signaling specificity. The Janus Kinases (JAKs) are a family of PTKs involved in signal transduction]pathways mediated by various cytokines. Initial characterization of JAKs showed no identifiable SH2 domain. However, we have found substantial evidence supporting the existence of an SH2 domain in JAKs through the use of various web-based computational analysis programs. Predictive secondary and tertiary structures recognize an SH2 domain in JAKs. In addition, a three-dimensional homology model was constructed using the SH2 domains of Src tyrosine kinase and Syp tyrosine phosphatase as templates. These results, in conjunction with preliminary binding studies showing interactions with tyrosine phosphorylated proteins in activated splenocytes, suggest a functional role for this domain in JAKs.