Members of the protein kinase C (PKC) family of serine/threonine protein kinases have been implicated in numerous cellular responses in a large variety of cell types. Expression patterns of individual members and differences in their cofactor requirements and potential substrate specificity suggest that each isoenzyme may be involved in specific regulatory processes. The PKCtheta isoenzyme exhibits a relatively restricted expression pattern with high protein levels found predominantly in hematopoietic cells and skeletal muscle. PKCtheta was found to be expressed in T, but not B lymphocytes, and to colocalize with the T-cell antigen receptor (TCR) at the site of contact between the antigen-responding T cell and the antigen-presenting cell (APC). Colocalization of PKCtheta with the TCR was selective for this isoenzyme and occurred only upon antigen-mediated responses leading to T-cell activation and proliferation. PKCtheta was found to be involved in the regulation of transcriptional activation of early-activation genes, predominantly AP-1, and its cellular distribution and activation were found to be regulated by the 14-3-3 protein. Other findings indicated that PKCtheta can associate with the HIV negative factor (Nef) protein, suggesting that altered regulation of PKCtheta by Nef may contribute to the T-cell impairments that are characteristic of infection by HIV. PKCtheta is expressed at relatively high levels in skeletal muscle, where it is suggested to play a role in signal transduction in both the developing and mature neuromuscular junction. In addition, PKCtheta appears to be involved in the insulin-mediated response of intact skeletal muscle, as well as in experimentally induced insulin resistance of skeletal muscle. Further studies suggest that PKCtheta is expressed in endothelial cells and is involved in multiple processes essential for angiogenesis and wound healing, including the regulation of cell cycle progression, formation and maintenance of actin cytoskeleton, and formation of capillary tubes. Here, we review recent progress in the study of PKCtheta and discuss its potential role in various cellular responses.