The consumption of fish and omega-3 fatty acids has been associated with reduced morbidity and mortality from coronary heart disease. The precise mechanisms by which fatty acids modulate atherosclerotic vascular disease remain to be defined. Experimental evidence suggests that fatty acids alter the function of the vascular endothelium, a metabolically active tissue that integrates signals between the circulation and the vascular wall. This review focuses on the effects of fatty acids on vascular endothelial nitric oxide production. Endothelial-derived nitric oxide regulates several vascular wall events that participate in the evolution of vascular disease. Impairment of endothelial nitric oxide production has been demonstrated in a variety of conditions such as smoking, diabetes, and hypertension that are risk factors for atherosclerosis. Evidence is reviewed that supports the postulate that both qualitative and quantitative alterations in circulating fatty acid species modulate vascular endothelial nitric oxide production. Although the mechanisms by which fatty acids alter vascular nitric oxide production remain obscure, fatty acid-mediated alterations in endothelial gene expression present a promising area for future investigation.