The effects of exogenous and endogenous cannabinoids on the cardiovascular system have been the focus of extensive research. The direct and indirect effects of cannabinoids on heart and blood vessels depend upon experimental conditions, animal species, and, in humans, clinical background. Cannabinoids decrease blood pressure in hypertensive rodents primarily because of decrease cardiac contractility, leading researchers to postulate a role in the treatment of hypertension and cardiac hypertrophy. Rimonabant, the CB(1) receptor blocker in clinical use in many countries, induced a marked and sustained increase in cardiac contractility and blood pressure in hypertensive rats but, on the contrary, contributed to decrease blood pressure in weight-loss clinical trials especially in obese patients with hypertension. In the midst of the obesity pandemic and from the cardiometabolic point of view, the overactivation of the endocannabinoid system present in intra-abdominal obesity appears to be very harmful. Moreover, novel human findings suggest a relationship between CB(1)-mediated overactive endocannabinoid system and nephrovascular damage. Overall, it appears that CB(1) blockade in obese patients behaves as a 'multiplier' of the many beneficial effects of body weight loss induced by a hypocaloric diet and increased physical activity (the 'lifestyle changes' that are so difficult to start and maintain). Thus, the concept - based mostly on experimental results using in vitro or animal models - that CB(1)-mediated endocannabinoid effects are beneficial for the cardiovascular system should be revised at least in obese patients. The results of long-term clinical trials such as the STRADIVARIUS and the CRESCENDO trials will tell whether the improvement in the cardiometabolic risk profile induced by Rimonabant translates into vascular changes, reducing the risk of myocardial infarction, stroke and cardiovascular death in patients with abdominal obesity. Time (and much more work) will tell us much more about cannabinoids and the human heart.