The endocannabinoid system (ECS) has emerged as one of the most relevant regulators of energy balance. The ECS acts through two cannabinoid receptors: types 1 and 2 (CB1 and CB2). CB1 receptors are widely expressed in the brain, but are also expressed in adipose tissue, skeletal muscle, the liver, the gut, and the pancreas. Blockade of CB1 receptors causes a reduction in food intake and a sustained weight loss. This system contributes also to the control of lipid and glucose metabolism, and it is well established that blockade of CB1 receptors enhances insulin sensitivity in both humans and rodents. In obese states, endocannabinoid levels are increased and might exert unfavorable effects on insulin-sensitive tissues. This review summarizes the effects of the endocannabinoid system on glucose metabolism in humans and rodents.