Overproduction of reactive oxygen species or increased oxidative stress is considered a major mechanism involved in the pathogenesis of endothelial dysfunction, the initiation and progression of atherosclerosis and its adverse events. Evidence supports the importance of nitric oxide derived from endothelial nitric oxide synthase as a vasoprotective substance, and of vascular NAD(P)H oxidase-derived reactive oxygen species as important signaling molecules in vascular cells. Recent studies show that dysfunction of endothelial nitric oxide synthase in atherosclerosis generates O(2)(-) rather than nitric oxide, and that upregulation of vascular NAD(P)H oxidase is closely associated with atherosclerotic progression and plaque instability.