Atherosclerosis and its major adverse cardiovascular events, heart disease and stroke, are the leading cause of morbidity and mortality worldwide. It is an inflammatory disease of the arteries, characterized by lesions containing immune cells, smooth muscle cells, lipids and extracellular matrix. Both innate and adaptive immunity are involved in atherosclerosis. In recent years, exciting discoveries have revolutionized our current understanding of the molecular pathways underlying the disease, providing potential new targets for clinical therapy. A dysregulation of the endocannabinoid system has been linked to a variety of pathologic conditions, including atherosclerosis and its related cardiovascular risk factors, obesity, dyslipidemia and diabetes. The endocannabinoid system comprises at least two distinct membrane receptors, CB1 and CB2, their endogenous ligands (named endocannabinoids) as well as enzymes for ligand biosynthesis and inactivation. It is well established that endocannabinoids are synthesized and released ‘‘on demand'' and that this process can be regulated both physiologically and under pathological conditions. As regards cardiovascular disease, blocking of CB1 receptors reduces several cardiometabolic risk factors in rodents and humans, indicating a potential relevance for the process of atherosclerosis. A modulation of endocannabinoid levels was reported in patients with coronary artery disease as well as in atherosclerotic mice. The first evidence for a causal role of endocannabinoid-mediated CB1 activation in atherosclerosis has been provided in an experimental mouse study. In vitro, CB1 antagonism mediated anti-inflammatory effects in macrophages and smooth muscle cells. The phytocannabinoid delta-9-tetrahydrocannabinol inhibited atherosclerotic plaque progression in mice, mainly by inhibiting macrophage recruitment. The effect was inhibited by CB2 antagonism. However, some controversy exists about the effects of genetic CB2 deficiency in atherosclerotic mice. In the future, more experimental studies should help to clarify whether the activated endocannabinoid system in this chronic disease indeed plays a causal role to increase the risk of acute thrombotic events or rather counterbalancing atherogenic processes. The existing data so far suggest opposing effects of CB1 and CB2 activation in the pathogenesis of atherosclerosis; however, the underlying cellular and molecular mechanisms remain largely elusive and deserve further investigations.