Protein kinase C (PKC)-epsilon was first discovered among novel PKC isotypes by cDNA cloning, and characterized as a calcium-independent but phorbol ester/diacylglycerol-sensitive serine/threonine kinase. PKC-epsilon is targeted to a specific cellular compartment in a manner dependent on second messengers and on specific adapter proteins in response to extracellular signals that activate G-protein-coupled receptors, tyrosine kinase receptors, or tyrosine kinase-coupled receptors. PKC-epsilon then regulates various physiological functions including the activation of nervous, endocrine, exocrine, inflammatory, and immune systems. The controlled activation of PKC-epsilon plays a protective role in the development of cardiac ischemia and Alzheimer's disease, whereas its uncontrolled chronic activation results in severe diseases such as malignant tumors and diabetes. This review summarizes recent progress in our understanding of the unique structure and physiological and pathological roles of PKC-epsilon with a focus mainly on knockout, transgenic, and mutational studies.