The amino acid l-arginine participates in a variety of key biochemical and physiological activities, including its well-recognized role as the key substrate for nitric oxide (NO) biosynthesis. The current review describes the cellular influences on arginine metabolism with particular focus on the transport of l-arginine in the endothelium. It details the processes by which intracellular and extracellular levels of l-arginine may influence nitric oxide production and further documents the imbalance that is evident in various cardiovascular disease states. In man, impairment of l-arginine transport has been observed in hypertension, heart failure, and renal disease, and it may thus be a relevant therapeutic target for rectification of nitric oxide pathogenesis in these conditions.