Plasma free fatty acid (FFA) levels are elevated in obesity. FFAs cause insulin resistance in all major insulin target organs (skeletal muscle, liver, endothelial cells) and have emerged as a major link between obesity, the development of the metabolic syndrome, and atherosclerotic vascular disease. FFAs also produce low-grade inflammation in skeletal muscle, liver, and fat, which may contribute to cardiovascular events. The challenges for the future include the prevention or correction of obesity and elevated plasma FFA levels through methods that include decreased caloric intake and increased caloric expenditure, the development of methods to measure FFAs in small blood samples, and the development of efficient pharmacologic approaches to normalize increased plasma FFA levels.