The translational product of the Vav proto-oncogene is exclusively expressed in cells of hematopoietic origin and is critical for lymphocyte development and activation. However, the biochemical basis of Vav’s function is unclear. Vav contains a single SH2 domain that is required for its association with the T cell receptor (TCR). Overexpression of Vav or SLP-76 in Jurkat cells leads to NFAT activation and IL-2 production. When co-expressed, Vav and SLP-76 synergize to induce a robust basal and TCR-mediated IL-2 response. Although SLP-76 does not contain a motif that would indicate it to be a member of the tyrosine, serine/threonine or lipid kinase families, it does contain several putative SH2/SH3-binding domains and has been shown to physically associate with the adapter protein GRB2 as well as PLC g1. The discovery of SLP-76 represents an important step in elucidating the mechanism of Vav transformation and TCR-mediated NFAT activation.