Nitric oxide (NO) regulates numerous physiological processes, including neurotransmission, smooth muscle contractility, platelet reactivity, and the cytotoxic activity of immune cells. Because of the ubiquitous nature of NO, inappropriate release of this mediator has been linked to the pathogenesis of a number of disease states. This provides the rationale for the design of therapies that modulate NO concentrations selectively. A well-characterized family of compounds are the inhibitors of NO synthase, the enzyme responsible for the generation of NO; such agents are potentially beneficial in the treatment of conditions associated with an overproduction of NO, including septic shock, neurodegenerative disorders, and inflammation. This article provides an overview of NO synthase inhibitors, focusing on agents that prevent binding of substrate L-arginine.