Oxidative stress seems to play a key-role in the pathogenesis of atherosclerosis. Intracellular ROS (reactive oxygen species) have been increasingly appreciated to have a role in this context. ROS seem to mediate various signaling pathways that underlie atherogenesis, from the initiation of fatty streak development through lesion progression to ultimate plaque rupture. Moreover enhanced oxidative stress has been found in many of the classical risk factors for cardiovascular disease. However some issues remain to be clarified. Agents that prevent LDL from oxidation have been shown in a range of in vitro and animal models to reduce the development and progression of atherosclerosis, but most of the trials with antioxidants, planned in the last years in patients with cardiovascular disease, have given equivocal results. The reason for the disappointing findings is unclear but one possible explanation is the lack of identification criteria of patients who are potentially candidates for antioxidant treatment. In this review we focused on potential source of ROS in atherosclerotic disease, the relationship between ROS generation and atherosclerotic progression and the potential role of antioxidants.