The classical cannabinoid receptors CB1 and CB2 as well as the cannabinoid-sensitive receptor GPR55 are widely distributed throughout the mammalian body. In the cardiovascular field, CB1 and CB2 crucially impact on diseases characterized by inflammatory processes, such as atherosclerosis and acute myocardial infarction. Both receptors and their endogenous ligands anandamide and 2-arachidonoylglycerol are up-regulated in the ischaemic heart in humans and animal models. Pharmacological and genetic interventions with CB1 and CB2 vitally affect acute ischaemia-induced cardiac inflammation. Herein, CB1 rather aggravates the inflammatory response whereas CB2 mitigates inflammation via directly affecting immune cell attraction, macrophage polarization and lymphocyte clusters in the pericardial adipose tissue. Furthermore, cannabinoids and their receptors affect numerous cardiac risk factors. In this context, cannabis consumption is debated to trigger arrhythmias and even myocardial infarction. Moreover, CB1 activation is linked to impaired lipid and glucose metabolism and therefore obesity and diabetes, while its antagonism leads to the reduction of plasma triglycerides, low-density lipoprotein cholesterol, leptin, insulin and glucose. On the other hand, activation of cannabinoid-sensitive receptors can also counteract unfavourable predictors for cardiovascular diseases. In particular, hypertension can be mitigated via CB1 agonism and impaired adrenoceptor responsiveness prevented by functional GPR55. Taken together, current insights identify the cannabinoid system as promising target not only to therapeutically interfere with the vasculature, but also to affect the heart as target organ. This review discusses current knowledge regarding a direct cardiac role of the cannabinoid system and points out its feasible therapeutic manipulation in the ischaemic myocardium. This article is part of a Special Issue entitled: Cardiomyocyte biology: new pathways of differentiation and regeneration edited by Marijke Brinkm, Marcus C. Schaub, and Christian Zuppinger.