There is compelling evidence that oxidative stress plays a key role in the pathophysiology of several major cardiovascular diseases. In atherosclerosis, hypertension, stroke, diabetes, and heart failure, expression of superoxide is increased in blood vessels, and endothelial vasomotor function is impaired, presumably caused in large part by inactivation of nitric oxide by superoxide. Endothelial dysfunction is predictive of cardiovascular risk, and probably plays a key role in the pathophysiology of atherosclerosis and its complications. In preliminary studies in hypercholesterolemic mice and in older humans, we have found high levels of superoxide in the aortic valve, as well as aorta. We speculate that superoxide, in addition to playing a key role in atherogenesis, may play a key role in signaling that leads to calcific aortic valvular stenosis. Antioxidant enzymes, especially the three isoforms of superoxide dismutase (SOD), modulate basal levels of superoxide and protect against vasomotor dysfunction. A common gene variant of extracellular SOD (ecSOD) is associated with increased risk of ischemic heart disease. We have made recombinant adenoviruses to examine cardiovascular effects of ecSOD and its heparin-binding domain. This approach might be used to study the almost 500 other proteins with a heparin-binding domain. Finally, several key unanswered questions in relation to oxidative stress and atherosclerosis are raised, and proposed as fruitful areas of research.