Several cardiometabolic factors present in obese and insulin-resistant individuals represent a continuum of increasing risk for the development of type 2 diabetes and cardiovascular disease. The importance of abdominal obesity as an independent risk factor is underscored by its association with adverse endocrine function. Recent evidence from animal and human studies has shown a role for the endocannabinoid system in maintaining energy balance and glucose and lipoprotein metabolism, with overactivity linked to aberrant glycemic and lipoprotein control, and a link to adiposity. Modulation of this system through endocannabinoid-receptor blockade has resulted in an improvement in a number of important risk factors in clinical trials, including visceral and subcutaneous abdominal adipose tissue, glucose tolerance, dyslipidemia and measures of inflammation. These findings may have significant implications for the management of patients at risk of developing cardiovascular and metabolic disease; however, the occurrence of psychiatric adverse events with rimonabant may preclude further development of centrally active endocannabinoid receptor antagonists for the treatment of cardiometabolic disorders. Future research is needed to explore the role of selective peripheral CB<sub>1</sub> receptor antagonists in the treatment of patients at high cardiometabolic risk.