Obesity has increased at a striking rate over the last 3 decades in the Western world. This negative trend dramatically affects physical health and, ultimately, cardiovascular risks. In fact, particularly at the visceral level, obesity is strongly associated with an increased risk for life-threatening conditions, such as type 2 diabetes mellitus, hypertension, dyslipidemia, and cardiovascular disease. Although nutritional changes and physical activity are commonly thought of as the core treatments for obesity, it is necessary to further support obese patients with a pharmacologic approach for 2 reasons: to reduce the metabolic risk profile, and to avoid the regaining of weight. Among the various pharmacologic targets explored in recent years, the endocannabinoid (EC) system now constitutes the most promising proposal so far. In this review, after focusing on the central and peripheral signaling pathways that preserve energy homeostasis, we review the role of the EC system in regulating food's rewarding properties, controlling caloric intake by acting in hypothalamic pathways, and in modulating metabolic functions of several peripheral organs. In addition, we provide evidence that supports the recently proposed hypothesis that a close association exists between obesity and overactivation of the EC system.