The wealth of existing epidemiologic evidence suggests that antioxidant intake limits the clinical expression of coronary artery disease. Because the oxidative modification of low-density lipoprotein is an important event in atherogenesis, it has been attractive to speculate that antioxidants act by limiting low-density lipoprotein orientation and, as a consequence, atherosclerotic lesion development. Early studies on animals also suggested that a number of structurally distinct antioxidant compounds could limit the extent of lesion development in animal models of atherosclerosis. More recently, however, secure evidence linking the antioxidant protection of low-density lipoprotein with a reduction in atherosclerosis has been elusive. This discrepancy may be explained by emerging evidence demonstrating that antioxidants may prove beneficial through tissue-specific effects that are not strictly related to the antioxidant protection of low-density lipoprotein.