T cells play a critical role in adaptive immune response. Defects or deregulation of T cell activation or function leads to immunodeficiencies or autoimmunity. Coordinated activation of T cells in response to antigen leads to activation, clonal expansion, and differentiation of antigen specific T cells. T cell activation is controlled by numerous signaling pathways initiated by T cell receptor (TCR) and costimulatory molecules (1). Biochemical signals initiated by TCR determine the specificity of T cell activation and the signaling pathways mediated by co-stimulatory molecules modulate the threshold for T cell activation (2). Protein kinase C isoforms are central components in signaling pathways that regulate numerous cellular processes in both adaptive and innate immunity (3). Protein kinase C (PKC) is a family of serine/threonine kinases that specifically phosphorylates its substrates at serine/threonine residues. There are 12 different isoforms in PKC family, and each one has unique roles in the regulation of cellular functions (4). PKC-θ is a member of novel PKCs that are Ca2+-independent PKC subfamily. PKC-θ is expressed primarily in T lymphocytes and muscle (5, 6). The critical role of PKC-θ in mediating T cell activation in vivo has been demonstrated by two-independently generated strains of knockout mice (7, 8). In both the cases, PKC-θ-/-naïve T cells displayed defects in T cell activation due to lack of NFAT, NF-κB and AP1 activation. Interestingly, thymocyte development is normal in PKC-θ-/-mice, suggesting the specific function of PKC-θ only in the peripheral T cells, and other isoforms of PKC might compensate for the loss of PKC-θ in thymocytes. Cell type specific function of PKC-θ is presumably mediated through the interactions with T cell specific factors that act to scaffold and selectively recruit PKC-θ during T cell antigenic stimulation (9). Studies using pharmacological reagents and knockout mice showed that PKC-θ specifically translocates to the immunological synapse (IS) upon CD3 crosslink (10). This review will detail the roles of PKC-θ in TCR-mediated signaling pathways. The important roles of PKC-θ in T cell mediated in vivo immune responses will also be discussed.