Upon T cell receptor (TCR) engagement, Lck (a member of the Src family of protein tyrosine kinases) phosphorylates immunoreceptor tyrosine-based activation motifs (ITAMs) contained within the cytoplasmic domains of the chains of the CD3 complex. Subsequently, Zap70 (a member of the Syk family of kinases) is recruited by binding of its Src homology 2 (SH2) domains to the phosphorylated ITAM sites. Activated Zap70 propagates signal transduction through the phosphorylation of downstream targets, including the adaptor molecules LAT and SLP-76. These adaptors facilitate phospholipase C-γ1 (PLCγ1) activation, resulting in the cleavage of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). The known signaling pathways that lead to T cell activation upon TCR engagement rely on IP3 and DAG second messengers. IP3 triggers calcium mobilization, which leads to activation of the transcription factor nuclear factor of activated T cells (NF-AT). DAG activates Ras guanine nucleotide-releasing protein (RasGRP) and protein kinase C θ (PKCθ), which in turn lead to activation of the Ras-mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways, respectively. CD45 and Csk have been identified as key proximal regulators of T cell signal transduction by modulating phosphorylation and, hence, enzymatic activity of the Src family kinases. The Connections Maps Pathway emphasizes the signaling events that lead to changes in gene expression in response to T cell activation.