Much progress has been made in understanding the function of protein kinase C-theta (PKCtheta) in the immune system since this Ca2+-independent PKC isotype was isolated in 1993 as an enzyme that is highly expressed in T lymphocytes and in muscle cells. Biochemical and genetic approaches revealed that, while dispensable for T-cell development, PKCtheta is required for the activation of mature T cells and for interleukin (IL)-2 production. This deficiency results from impaired receptor-induced stimulation of the transcription factors AP-1 and NF-kappaB. PKCtheta integrates T-cell receptor (TCR)/CD28 costimulatory signals, which are essential for productive T-cell activation and, most likely, for prevention of T-cell anergy. A unique property of PKCtheta is its highly selective recruitment to the central supramolecular activation complex (cSMAC) region of the immunological synapse (IS) in antigen-stimulated T cells. Our work revealed that this highly selective localization is not entirely dependent on phospholipase C (PLC) activity and diacylglycerol (DAG) production. Instead, a novel signaling pathway that requires functional Vav1, phosphatidylinositol 3-kinase (PI3-K), the small GTPase Rac and actin cytoskeleton reorganization regulates the localization and, perhaps, activation of PKCtheta. PKCtheta also provides a survival signal, which protects T cells from apoptosis. Additional work is required to identify the immediate targets of PKCtheta and its immune functions in vivo. This work is likely to validate PKCtheta as an attractive drug target.