L-arginine is the substrate of endothelial nitric oxide synthase and the main precursor of nitric oxide in the vascular endothelium, thus its effects are mediated largely by increases in nitric oxide production. L-arginine has antioxidant and antiapoptotic properties, increases smooth muscle relaxation, inhibits the expression of adhesion molecules and chemotactic peptides, decreases endothelin-1 expression, and inhibits platelet aggregation. This amino acid also improves endothelial function in patients with coronary artery disease and dilates human epicardial atheromatous coronary arteries. Despite the positive results from small case-control studies, it is still unclear whether chronic administration of L-arginine has any effect on clinical outcome in patients with coronary artery disease. In addition, other indirect strategies, such as the inhibition of arginase, could prove more effective at improving intracellular L-arginine bioavailability than exogenous L-arginine administration. The potential clinical usefulness of L-arginine, therefore, needs further evaluation in large, prospective clinical trials. Here, we present a critique of the existing literature about the role of L-arginine in the prevention of atherosclerosis.