Abstract: Protein kinase C (PKC) is a family of multifunctional isozymes that plays an important role in the regulation of intracellular insulin signal transduction in various insulin‐sensitive tissues. This article highlights current understanding on the mechanism of PKC‐induced insulin resistance in skeletal muscle, a major target site for insulin‐mediated glucose disposal. Initial, apparently contradictory findings on the role of PKC on insulin action can be explained on the basis that certain PKC isoforms (e.g., ‐ζ and ‐λ) have been identified as downstream targets of PI3‐kinase activation, while DAG‐sensitive PKCs (e.g., ‐θ and ‐ε) have negative regulatory effects on insulin signaling. Hence, pharmacological therapies targeting specific PKC isoforms could enhance insulin action and improve glycemic control in patients with impaired glucose tolerance and overt diabetes.