Oxidative stress has been recognized as a key mechanism in the development of vascular damage, particularly atherosclerosis. In spite of substantial experimental evidence demonstrating reversal of endothelial dysfunction and prevention of atherosclerosis in experimental settings, no benefits have been observed in large clinical trials in which antioxidants have been given in high-risk patients for the prevention of cardiovascular events. Evaluation of the clinical relevance of the oxidative modification hypothesis requires identification of potential molecular targets of antioxidant interventions and effective antioxidant agents. Future research should necessarily consider quantification of interindividual variations in oxidative stress using appropriate biomarkers.