The endogenous cannabinoid system plays a vital role in appetite, energy homeostasis and the cardiovascular system. Emerging clinical data have shown that selective cannabinoid antagonism of cannabinoid receptors (CB1) using the anti-obesity drug, rimonabant, can reduce cardio-metabolic risk factors in patients. Metabolic improvements observed in several trials are consistent, showing beneficial effects on lipid ratios, glucose control and vascular function, as well as an improvement in other cardio-metabolic biomarkers. Cannabinoid receptors are ubiquitous: the endocannabinoid system is conserved in many organs important to homeostasis control, including the liver, pancreas, skeletal muscle and adipose tissue. The cardiovascular effects of endocannabinoids are mediated through receptors in blood vessels, myocardial cells and platelets, causing changes in vascular tone, heart rate and haemostatic function. Endogenous and exogenous cannabinoids increase platelet aggregation, suggesting that antagonism might have an anti-thrombotic effect. Vasodilator and anti-thrombotic therapies are commonly prescribed to patients with cardiovascular disease, and therefore CB1 receptor antagonists offer great promise as a multi-faceted therapeutic agent. This article reviews the current position reached from cannabinoid studies, with particular reference to the cardiovascular effects of endocannabinoid blockade and the potential future uses of endocannabinoid receptor blockade with drugs such as rimonabant.