Diabetes mellitus produces a state of chronic hyperglycemia which in turn leads to the development of severe complications including retinopathy, nephropathy, neuropathy, and atherosclerosis. Many different mechanisms have been put forward to attempt to explain how glucose elevations can damage these various organ systems. Protein kinase C activation is one of the sequelae of hyperglycemia and is thought to play a role in the development of diabetic complications. There are multiple mechanisms for its activation in the diabetic state and multiple downstream effects attributable to that activation. The role of protein kinase C activation in the development of the above-mentioned complications of diabetes is discussed in this chapter. In addition, the potential use of isoform-specific inhibitors of protein kinase C for the treatment of diabetic complications is proposed.