The gaseous free radical nitric oxide is an important biologic mediator with physiologic and pathophysiologic roles in nearly every organ system. Because of its unique biologic activity, unusual chemical structure, and unprecedented mechanisms of action, nitric oxide, arguably more than any other natural product, has opened new avenues to investigate cellular processes. Nitric oxide is generated in biologic tissues by specific nitric oxide synthases that metabolize arginine and molecular oxygen to citrulline and nitric oxide. Besides its function as a diffusible messenger in the vasculature and in neurons, nitric oxide also plays a key role in innate immunity and inflammation. Recent progress has allowed the identification of the nitric oxide pathway in several cell types that reside in the skin, including keratinocytes, melanocytes, Langerhans cells, fibroblasts, and endothelial cells. Convincing evidence suggests that nitric oxide synthesis in these cells can be modulated by calcium-mobilizing agonists as well as diverse inflammatory and immune stimuli, and thereby contributes to the pathogenesis of several human skin diseases. Characterization of these intrinsic and extrinsic regulatory stimuli of nitric oxide synthesis has afforded substantial insights into the role of nitric oxide in inflammatory, hyperproliferative, and autoimmune skin diseases, as well as skin cancer, and may ultimately form the basis for future therapeutic intervention. The demonstrable and potential roles of nitric oxide in skin disease pathogenesis and treatment are the subjects of this review.