Endothelial dysfunction is characterized by a vasoconstrictive and prothrombotic state in the vasculature; it plays a role in all stages of cardiac disease and is a significant independent predictor of cardiovascular outcomes. Nitric oxide (NO) performs multiple biologic activities in the endothelium, including vasodilation and antithrombotic actions. Reduced NO bioactivity is a major component of endothelial dysfunction. Impaired NO bioactivity is an important factor in the pathogenesis of atherosclerosis and in the metabolic syndrome. The functions of NO bioactivity in the heart go well beyond those in the endothelium, as all 3 NO synthase (NOS) isoforms-endothelial NOS, neuronal NOS, and inducible NOS-are expressed in cardiac myocytes and mediate systolic, diastolic, and chronotropic cardiac functions. Impairment of NO bioactivity is a pathogenic factor in various forms of cardiac disease. Although these findings support the potential use of NO-targeted therapies for treatment of cardiac disease, the complexities of the biologic actions of NO in the vasculature and heart are such that development of therapies is still largely in the preliminary stages.