The free radical theory of aging posits that oxidative stress is among the major mechanisms in aging and age-related disease, including cardiovascular disease (CVD). Numerous in vitro and animal studies have supported the role of low-density lipoprotein (LDL) oxidation in atherosclerosis. This has led to the hypothesis that antioxidants could be used as an inexpensive means of prevention and possibly, treatment of coronary artery disease, stroke, peripheral vascular disease, and other CVD-related diseases. Epidemiologic cohort studies with large numbers of men, women, and diverse populations have been largely supportive of this hypothesis. However, interventional trials have been controversial, with some positive findings, many null findings, and some suggestion of harm in certain high-risk populations. Because of the mismatch between the epidemiologic studies and the interventional trials, some researchers have advocated ending antioxidant work. Others have questioned the validity of the LDL oxidative hypothesis itself. Clearly, further research is needed to understand the reasons for the mismatch between the epidemiologic and interventional work. Recent smaller interventional studies with carefully chosen populations, such as those under high levels of oxidative stress, have yielded largely positive results. This suggests that we need more hypothesis-driven and rigorous clinical trial designs. This should help clarify the true potential utility of antioxidants in CVD and may lead to a better understanding of the role of oxidative stress in atherosclerosis.