Obesity, the metabolic syndrome, diabetes and cardiometabolic risk are increasing at epidemic rates worldwide. Without interventions, the healthcare ramifications and costs of this epidemic will be astronomical. Current available treatment modalities have demonstrated limited effectiveness to deal with this metabolic epidemic. A novel metabolic pathway, the endocannabinoid system, plays a significant and direct role in appetite regulation, glucose homeostasis and lipid metabolism. Activation of the endocannabinoid system increases hunger and decreases satiety, and promotes insulin resistance and lipogenesis. Studies indicate that the endocannabinoid system is chronically activated in abdominal obesity and Type 2 diabetes. Additionally, blockade of the endocannabiniod receptor type-1 improves multiple cardiometabolic parameters and may represent a potential mechanism to combat obesity, metabolic syndrome, diabetes and other cardiometabolic risks. Rimonabant, a novel agent, blocks the endocannabinoid-receptor type 1, and results in weight loss, decreases in abdominal adiposity, improvement in glucose and lipid homeostasis and decreases components of the metabolic syndrome. It is the first therapeutic agent that inhibits the endocannabiniod system and improves multiple cardiometabolic parameters.