L-arginine is a precursor for nitric oxide (NO) synthesis. NO is a ubiquitous mediator that is formed by a family of enzymes named NO synthases. In the brain, NO acts as a neurotransmitter; in the immune system, NO acts as a mediator of host defense; and in the cardiovascular system, NO mediates the protective effects of the intact endothelium, acting as a vasodilator and endogenous antiatherogenic molecule. About 5 g of L-arginine is ingested each day in a normal Western diet. L-arginine plasma levels are not significantly reduced in most disease conditions, except end-stage renal failure during hemodialysis treatment. Nonetheless, intravenous or dietary (oral) administration of relatively large doses of L-arginine has been shown to result in enhanced NO formation in subjects with impaired endothelial function at baseline. In several controlled clinical trials, long-term administration of L-arginine has been shown to improve the symptoms of cardiovascular disease. However, in other trials L-arginine was not beneficial, and in a recent study, the authors reported higher mortality of subjects receiving L-arginine than those receiving placebo. Recently it became clear that endogenous levels of asymmetric dimethylarginine (ADMA), a competitive inhibitor of L-arginine metabolism by NO synthase, may determine a subject's response to L-arginine supplementation. L-arginine appears to exert no effect in subjects with low ADMA levels, whereas in subjects with high ADMA levels, L-arginine restores the L-arginine/ADMA ratio to normal levels and thereby normalizes endothelial function. In conclusion, the effects of L-arginine supplementation on human physiology appear to be multicausal and dose-related. Doses of 3-8 g/d appear to be safe and not to cause acute pharmacologic effects in humans.