Abstract The endothelium synthesizes and releases nitric oxide (NO) to maintain homeostatic function. Under basal conditions, endothelium-derived NO maintains a nonthrombogenic surface, prohibits leukocyte attachment, and promotes vascular relaxation. In the setting of clinical syndromes associated with the development of atherothrombosis, there is decreased bioavailable NO owing to diminished synthesis and release in addition to increased generation of reactive oxygen species. These biochemical changes perturb significantly vascular homeostatic mechanisms and promote platelet aggregation, inflammatory cell diapedesis, and vasoconstriction. Endothelial dysfunction may be evaluated using invasive and/or noninvasive techniques, including coronary artery reactivity to acetylcholine and brachial artery ultrasonography, respectively. NO replacement therapies may be initiated to restore deficits associated with dysfunctional endothelium. Strategies to replenish bioavailable NO include the administration of organic nitrosovasodilators or NO donor compounds, therapies to improve NO synthase function, and gene therapy.