The article discusses the structural basis of protein kinase C (PKC) isoform function, focusing on the structural determinants that dictate differences in enzymology, subcellular targeting, protein-protein interactions, and downregulation among PKC isoforms. PKC isoforms are modular enzymes with a regulatory domain containing membrane-targeting motifs and a conserved catalytic domain that binds ATP and substrates. These enzymes are coexpressed in many cell types and respond to similar stimulatory agonists, but individual isoforms have unique functions due to differences in subcellular compartmentalization, protein-protein interactions, and posttranslational modifications. The review highlights the structural basis for differences in lipid cofactor responsiveness, regulatory phosphorylations, and intra-/intermolecular interactions that control PKC activation and subcellular targeting. It also discusses the structural features of PKC isoforms, including the C1 and C2 domains, which are critical for lipid binding and membrane targeting. The C1 domain is involved in binding DAG and PMA, while the C2 domain binds anionic phospholipids in a calcium-dependent manner. The review also covers the role of PKC interactions with RACK proteins, which are essential for isoform-specific cellular responses. The C1 and C2 domains are discussed in detail, including their structural features, lipid binding affinities, and roles in subcellular targeting. The review emphasizes the importance of understanding the unique molecular features of PKC isoforms to design novel isoform-specific activator or inhibitor compounds for therapeutic applications.The article discusses the structural basis of protein kinase C (PKC) isoform function, focusing on the structural determinants that dictate differences in enzymology, subcellular targeting, protein-protein interactions, and downregulation among PKC isoforms. PKC isoforms are modular enzymes with a regulatory domain containing membrane-targeting motifs and a conserved catalytic domain that binds ATP and substrates. These enzymes are coexpressed in many cell types and respond to similar stimulatory agonists, but individual isoforms have unique functions due to differences in subcellular compartmentalization, protein-protein interactions, and posttranslational modifications. The review highlights the structural basis for differences in lipid cofactor responsiveness, regulatory phosphorylations, and intra-/intermolecular interactions that control PKC activation and subcellular targeting. It also discusses the structural features of PKC isoforms, including the C1 and C2 domains, which are critical for lipid binding and membrane targeting. The C1 domain is involved in binding DAG and PMA, while the C2 domain binds anionic phospholipids in a calcium-dependent manner. The review also covers the role of PKC interactions with RACK proteins, which are essential for isoform-specific cellular responses. The C1 and C2 domains are discussed in detail, including their structural features, lipid binding affinities, and roles in subcellular targeting. The review emphasizes the importance of understanding the unique molecular features of PKC isoforms to design novel isoform-specific activator or inhibitor compounds for therapeutic applications.