Oxidant stress in the cardiovascular system may occur when antioxidant capacity is insufficient to reduce reactive oxygen species and other free radicals. Oxidant stress has been linked to the pathogenesis of atherosclerosis and incident coronary artery disease. As a result of this connection, early observational studies focused on dietary antioxidants, such as β-carotene, α-tocopherol, and ascorbic acid, and demonstrated an inverse relationship between intake of these antioxidants and major adverse cardiovascular events. These findings supported a number of randomized trials on the use of selected antioxidants as primary or secondary prevention strategies to decrease cardiac risk; however, many of these studies reported disappointing results with little or no observed risk reduction in antioxidant-treated patients. Several plausible explanations for these findings have been suggested, including incorrect antioxidant choice or dose, synthetic versus dietary antioxidants as the intervention, and patient selection, all of which will be important to consider when designing future clinical trials. This review will focus on the contemporary evidence that is the basis for our current understanding of the role of antioxidants in cardiovascular disease prevention.