The zeta isotype of protein kinase C (PKCzeta) is a member of the atypical PKC subfamily and has been widely implicated in the regulation of cellular functions. Increasing evidence from studies using in vitro and in vivo systems points to PKCzeta as a key regulator of critical intracellular signaling pathways induced by various extracellular stimuli. The major activation pathway of PKCzeta depends on phosphatidylinositol (PI)-3,4,5-trisphosphate (PIP(3)), which is mainly produced by PI-3 kinase. 3'-PI-dependent protein kinase 1, which binds with high affinity to PIP(3), phosphorylates and activates PKCzeta. Many studies demonstrated the involvement of PKCzeta in the mitogen-activated protein kinase cascade, transcriptional factor NFkappaB activation, ribosomal S6-protein kinase signaling, and cell polarity. An important molecular event in a cell is the association of PKCzeta with other signaling molecules, as well as scaffold proteins, to form large complexes that regulate their pathways. The understanding of the mechanisms underlying PKCzeta-mediated control of intracellular signaling is beginning to provide important insights into the roles of PKCzeta in various cells.