SUMMARY Lipotoxicity, caused in large part by overnutrition, directly leads to endothelial dysfunction. Excess lipids in both the circulation and at the tissue level contribute to endothelial dysfunction that underlies much of the pathophysiology of both metabolic disease, including obesity and diabetes and their CV complications. Direct lipotoxic effects on other organs as well as secondary insults from endothelial dysfunction synergize to cause substantial morbidity and mortality. Lifestyle interventions, including reduced calorie intake, diet, and exercise as well as a variety of pharmacologic interventions targeting various mechanisms underlying lipotoxicity in vascular endothelium significantly modify metabolic and CV risk.