The oxidative hypothesis of cardiovascular disease (CVD) has undergone tremendous changes during the past few years. Innumerable new proatherogenic effects have been added to the existing list that could be attributed to oxidative stress. However, both animal and human trials with a variety of antioxidants have failed to establish unambiguously a protective role for antioxidants in the prevention of CVD. This could be because of poor choice and dosage of antioxidants, incompatible experimental models, oxidative metabolism of the antioxidant, unrealistic expectations, and other reasons. More importantly, recent studies suggest that oxidative stress also could induce antioxidant enzymes in both cell culture and in vivo systems. In lieu of the potential of known deterrents of CVD such as exercise, estrogens, and the consumption of polyunsaturated fatty acids to induce an oxidative stress, the possibility that natural enhancement of antioxidant defense in the artery could better serve to deter CVD cannot be ignored. Thus, if oxidative stress does play a role in CVD, it may be better, in the absence of suitable animal models that respond to antioxidants, to adhere to behavioral and dietary changes that have been shown to benefit CVD.