Cardiovascular disease is a major cause of morbidity and mortality worldwide. Innovative new treatment options for this cardiovascular pandemic are urgently needed. Activation of purinergic receptors (PRs) is critically involved in the development and progression of cardiovascular disease including atherosclerosis, ischemic heart disease, hypertension, and diabetes. PRs have been targeted for the treatment of several cardiovascular diseases in a clinical setting. The P2YR antagonists such as clopidogrel, ticagrelor, and others are the most successful class of purinergic drugs targeting platelets for the treatment of acute coronary syndrome. In addition to targeting platelets, ticagrelor may exert P2YR-independent effect by targeting erythrocyte-mediated purinergic activation. The partial AR agonist neladenoson and the AR agonist regadenoson have been applied in cardiovascular medicine. In experimental studies, many other PRs have been shown to play a significant role in the development and progression of cardiovascular diseases, and targeting these receptors have resulted in promising outcomes. Therefore, many of these PRs including AR, AR, P2XR, P2XR, P2XR, P2YR, P2YR, P2YR, and P2YR can be considered as therapeutic targets. However, the multitude of PR subtypes expressed in different cells of the cardiovascular system may constitute a challenge whether single or multiple receptors should be targeted at the same time for the best efficacy. The present review discusses the promising purinergic drugs used in clinical studies for the treatment of cardiovascular disease. We also update experimental evidence for many other PRs that can be considered as therapeutic targets for future drug development.