Oxidative stress is implicated in the pathogenesis of many card-iovascular diseases, including hypercholesterolemia, atherosclerosis, hypertension, diabetes, and heart failure. One of the major antioxidant enzymes in the vessel wall is extracellular superoxide dismutase (ecSOD). Over the past ten years our laboratory has demonstrated that ecSOD expression is transcriptionally or posttranscriptionally regulated by nitric oxide, angiotensin II, and exercise training, all of which are implicated in various cardiovascular diseases. Most re-cently, we discovered that a copper chaperone for ecSOD plays an essential role in regulating ecSOD expression and activity as well as cell growth in vitro and in vivo. Using gene targeting in mice and molecular and cell biological approaches, we are currently investigating 1) how ecSOD activity is regulated and 2) how copper regulates cell proliferation in cancer as well as in cardiovascular disease.