Endothelial dysfunction, characterized by a loss in nitric oxide bioactivity, is an early event in the development of atherosclerosis and determines future vascular complications. Emerging evidence suggests a causal role for oxidative stress in this process. Reactive oxygen species can directly inactivate nitric oxide, modulate protein function and act as cellular signaling molecules. These events contribute to the initiation and progression of endothelial dysfunction. Considerable data also indicates that antioxidant compounds limit oxidative damage and restore endothelial function. The purpose of this review is to discuss these data and suggest novel approaches for lowering the oxidative stress in the vasculature.