Cardiovascular diseases (CVD) are still the most frequent cause of death in Western Europe. Pathophysiological experiments revealed in the last years that the vascular endothelium, as well as a result of the synthesis of nitric oxide (NO), is a crucial regulator of vascular function and homeostasis. The vascular endothelium plays a key role in cardiovascular physiology and pathophysiology, largely via NO-dependent processes. L-Arginine is the substrate for the endothelial NO synthase (eNOS) to generate NO. Endothelial dysfunction is caused by various cardiovascular risk factors. In most studies, acute and chronic administration of L-arginine has been shown to improve endothelial function in animal models of hypercholesterolemia and atherosclerosis. Therefore, numerous studies have been conducted to elucidate whether dietary L-arginine supplementation can augment NO production in humans and thereby improve endothelium-dependent vasodilatation. The most likely mechanism that explains the occurrence of endothelial dysfunction and the effect of L-arginine is that application of L-arginine antagonizes asymmetric dimethylarginine (ADMA), the endogenous NO synthase (NOS) inhibitor. This could solve the L-arginine paradox namely that L-arginine improves NO-mediated vascular function in vivo, although its baseline plasma concentration is about 25- to 30-fold higher than the Michaelis-Menten constant Km of the isolated, purified eNOS in vitro. Recent findings suggest that large, prospective, randomized clinical trials might be needed to identify those patients who are the most likely to benefit from L-arginine. Testing patients for ADMA and L-arginine plasma levels for calculating the L-arginine/ADMA ratio might be an adequate strategy.