Although rimonabant has been approved for use in several countries, the Food and Drug Administration has expressed concern about the potential for adverse neurologic and psychiatric effects, considering the widespread distribution of CB1 receptors in the brain. While more research is clearly needed, the clinical evidence shows that CB1-receptor blockade with rimonabant improves multiple cardiovascular and metabolic variables, including body weight and waist circumference, HDL-C, triglycerides, and glucose metabolism. Furthermore, these effects, which are probably mediated by both peripheral and central actions in the ECS, appear to be greater than the improvements that would be expected from weight loss alone. There are multiple ongoing and planned studies with rimonabant as well as several other CB-receptor blockers (e.g., taranabant, CP-945,598). While diet and exercise are the cornerstones of cardiometabolic risk-factor reduction, improved pharmacotherapies are urgently needed. The ECS has provided us with new insights and a promising new avenue for the management of obesity and its associated cardiometabolic risk factors.