The ζ isotype of protein kinase C (PKCζ) 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 PKCζ as a key regulator of critical intracellular signaling pathways induced by various extracellular stimuli. The major activation pathway of PKCζ depends on phosphatidylinositol (PI)-3,4,5-trisphosphate (PIP3), which is mainly produced by PI-3 kinase. 3′-PI-dependent protein kinase 1, which binds with high affinity to PIP3, phosphorylates and activates PKCζ. Many studies demonstrated the involvement of PKCζ in the mitogen-activated protein kinase cascade, transcriptional factor NFκB activation, ribosomal S6-protein kinase signaling, and cell polarity. An important molecular event in a cell is the association of PKCζ with other signaling molecules, as well as scaffold proteins, to form large complexes that regulate their pathways. The understanding of the mechanisms underlying PKCζ-mediated control of intracellular signaling is beginning to provide important insights into the roles of PKCζ in various cells.