Abstract: Over the past 50 years, the recreational use of Cannabis sativa increased enormously, especially in the young population. The main psychoactive and euphoric effects of Cannabis sativa are due to Δ-9-tetrahydrocannabinol. Once cannabinoid receptors, CB1 and CB2, were discovered to be distributed in the cardiovascular system, this was the starting point to assess the effects of Cannabis sativa on vascular endothelium. The aim of this review is to focus attention on the role of cannabinoids in endothelial dysfunction. The CB1 receptor seems to have a pro-atherogenic profile while the CB2 receptor acts to counteract the onset of atherosclerosis. In addition, several lines of evidence (e.g., epidemiological studies, clinical trials and animal studies) correlate marijuana smoking to a worsening of angina pectoris and the onset of acute coronary syndromes. It has been demonstrated that endothelial dysfunction plays a crucial role in the pathogenesis and progression of atherosclerosis. Cannabinoids and their receptors can play an important role in the alterations of endothelial function and morphologies, thus in the advance of atherosclerotic process.