Type 2 diabetes is closely related to abdominal obesity and is generally associated with other cardiometabolic risk factors, resulting in a high incidence of cardiovascular complications. Several animal and human observations suggest that the endocannabinoid (EC) system is overactivated in presence of abdominal obesity and/or diabetes, and contributes to disturbances of energy balance and metabolism. Not only it regulates the intake of nutrients through central mechanisms located within the hypothalamus and limbic area, but it also intervenes in transport, metabolism and deposit of the nutrients in the digestive tract, liver, adipose tissue, skeletal muscle, and possibly pancreas. Activation of both central and peripheral CB1 receptors promotes weight gain and associated metabolic changes. Conversely, rimonabant, the first selective CB1 receptor antagonist in clinical use, has been shown to reduce body weight, waist circumference, triglycerides, blood pressure, insulin resistance and C-reactive protein levels, and to increase HDL cholesterol and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. In addition, a 0.5-0.7% reduction in glycated hemoglobin (HbA1c) levels was observed in metformin- or sulfonylurea-treated patients with type 2 diabetes and in drug-naive or insulin-treated diabetic patients. Almost half of metabolic changes occurred beyond weight loss, in agreement with direct peripheral effects. Rimonabant was generally well-tolerated, but with a slightly higher incidence of depressed mood disorders, anxiety, nausea and dizziness compared to placebo. New trials are supposed to confirm the potential role of rimonabant (and other CB1 neutral antagonists or inverse agonists) in overweight/obese patients with type 2 diabetes and high risk cardiovascular disease.