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Vascular disease associated with diabetes mellitus is a major cause of morbidity and mortality and is increasing in the United States. It is now recognized that oxidative stress plays a substantial role in the underlying vascular pathology of several diseases, including hypertension and diabetes. In diabetes, there is an increase in the steady state levels of reactive oxygen species. One of the primary generators of reactive oxygen species is nicotinamide adenine dinucleotide phosphate oxidase. Studies have indicated that inhibition of this system is associated with vascular benefits in diabetes. Therefore, there may be a role for therapies directed at nicotinamide adenine dinucleotide phosphate oxidase in this disease. This review will examine the structure, activation, potential role in vascular disease, and benefits of inhibition of nicotinamide adenine dinucleotide phosphate oxidase.