Obesity and cardiometabolic risk continue to be major public health concerns. A better understanding of the physiopathological mechanisms leading to obesity may help to identify novel therapeutic targets. The endocannabinoid system discovered in the early 1990s is believed to influence body weight regulation and cardiometabolic risk factors. This article aims to review the literature on the endocannabinoid system including the biological roles of its major components, namely, the cannabinoid receptors, their endogenous ligands the endocannabinoids and the ligand-metabolising enzymes. The review also discusses evidence that the endocannabinoid system constitutes a new physiological pathway occurring in the central nervous system and peripheral tissues that has a key role in the control of food intake and energy expenditure, insulin sensitivity, as well as glucose and lipid metabolism. Based on the important finding that there is a close association between obesity and the hyperactivity of the endocannabinoid system, interest in blocking stimulation of this pathway to aid weight loss and reduce cardiometabolic risk factor development has become an important area of research. Among the pharmacological strategies proposed, the antagonism of the cannabinoid receptors has been particularly investigated and several clinical trials have been conducted. One challenging pharmacological task will be to target the endocannabinoid system in a more selective, and hence, safe way. As the management of obesity also requires lifestyle modifications in terms of healthy eating and physical activity, the targeting of the endocannabinoid system may represent a novel approach for a multifactorial therapeutic strategy.