Protein kinase C (PKC) isoforms are a family of lipid-activated enzymes involved in various cellular functions. These enzymes consist of a regulatory domain and a conserved catalytic domain. While PKCs are coexpressed and respond to similar agonists, individual isoforms exhibit unique functions due to differences in subcellular localization, protein-protein interactions, and posttranslational modifications. This review focuses on the structural basis for these differences, including lipid cofactor responsiveness, regulatory phosphorylations, and intra-intermolecular interactions. Understanding these molecular features can inform the design of novel PKC-specific activators or inhibitors for therapeutic applications. The review covers the structure of PKC isoforms, their activation and localization mechanisms, and the role of RACK proteins in PKC regulation. It also delves into the C1 and C2 domains, which mediate membrane targeting and lipid binding, respectively, and discusses the importance of tyrosine phosphorylation in PKC function.Protein kinase C (PKC) isoforms are a family of lipid-activated enzymes involved in various cellular functions. These enzymes consist of a regulatory domain and a conserved catalytic domain. While PKCs are coexpressed and respond to similar agonists, individual isoforms exhibit unique functions due to differences in subcellular localization, protein-protein interactions, and posttranslational modifications. This review focuses on the structural basis for these differences, including lipid cofactor responsiveness, regulatory phosphorylations, and intra-intermolecular interactions. Understanding these molecular features can inform the design of novel PKC-specific activators or inhibitors for therapeutic applications. The review covers the structure of PKC isoforms, their activation and localization mechanisms, and the role of RACK proteins in PKC regulation. It also delves into the C1 and C2 domains, which mediate membrane targeting and lipid binding, respectively, and discusses the importance of tyrosine phosphorylation in PKC function.