Overproduction of superoxide by the mitochondrial electron transport chain is the common link between the various pathways of glucotoxicity. The increased oxidative byproducts in diabetes are the result of a glucose-induced increase in the production of reactive oxygen species and decreased antioxidant defense capacity. Several epidemiologic observations indicate an inverse association between vitamin E intake and coronary heart disease (CHD). There are several limitations in such studies including the fact that they rely on food questionnaires and dietary recalls. Large interventional trials have yielded inconsistent results. Of concern is that, in some of these studies there was a greater incidence of lung cancer or CHD. These observations underscore the potential hazards of consuming large amounts of antioxidants. At the present time, given the inconsistencies of the studies available, the widespread supplementation with pharmacological doses of antioxidants should be discouraged. Future studies should focus on identifying reliable markers of oxidation to incorporate these measurements in the clinical interventional trial.