Vascular endothelial dysfunction is determined by both genetic and environmental factors that cause decreased bioavailability of the vasodilator nitric oxide. This is a hallmark of atherosclerosis, hypertension, and coronary heart disease, which are major complications of metabolic disorders, including diabetes and obesity. Several therapeutic interventions, including changes in lifestyle as well as pharmacologic treatments, are useful for improving endothelial dysfunction in the face of lipotoxicity. This review discusses the current understanding of molecular and physiologic mechanisms underlying lipotoxicity-mediated endothelial dysfunction as well as relevant therapeutic approaches to ameliorate dyslipidemia and consequent endothelial dysfunction that have the potential to improve cardiovascular and metabolic outcomes. © 2012 Elsevier Inc.