Studies have found the association between hypercholesterolemia with oxidative stress and atherogenesis. Atherosclerosis has become one of the leading causes of mortality among industrial countries due to abnormal cholesterol metabolism, inflammation of arterial wall and build-up of atherosclerotic plaque. This disease has been recently linked with alpha lipoic acid (ALA), a mitochondrial compound with antioxidative effects in water- and fat-soluble mediums, in both oxidized and reduced forms: lipoic acid (LA) and dihydrolipoic acid (DHLA), respectively. This article provides a comprehensive review of the development and progression of atherosclerosis and the roles and regulations of ALA as a potent antioxidant against atherosclerosis.