Over the past 15 years, research on the endogenous cannabinoid (CB) system—now usually referred to as the endocannabinoid system (ECS)—has identified the significant effects of the ECS on the regulation of food intake and lipid and glucose metabolism in animals and humans. Endocannabinoids are endogenous lipids capable of binding to endogenous CB₁ and CB₂ receptors. CB₁ receptors are present in the hypothalamic nuclei, which are involved in the control of energy balance and body weight, and in the mesolimbic system, which mediates the motivation to consume palatable food, as well as in adipocytes, the gut, and the liver. In the recent Rimonabant in Obesity (RIO)-Europe study, treatment with the first CB₁ receptor antagonist, rimonabant, led to sustained, clinically meaningful weight loss and a reduction in waist circumference. Patients treated with rimonabant also demonstrated statistically significant improvement in high-density lipoprotein cholesterol levels, triglyceride levels, and insulin resistance, as well as a reduced overall prevalence of metabolic syndrome. Results of this and other studies support the role of endocannabinoids in the development and maintenance of obesity. In addition, these findings suggest that CB₁ receptor antagonists such as rimonabant may offer a potential new approach to managing obesity and associated cardiometabolic risk factors.