Platelets express a wide range of receptors and proteins that play essential roles in thrombus formation. Among these, the P2Y12 receptor, a member of the G protein-coupled receptor family, has attracted a significant amount of attention. Stimulation of the P2Y12 receptor by ADP results in activation of various signaling pathways involved in amplification of platelet activation and aggregation. There have been extensive attempts to design an ideal antithrombotic agent to block P2Y12, which shows selective expression, as an intervention for cardiovascular disease. Current inhibitors of the P2Y12 receptor include indirect inhibitor members of the thienopyridine family (ticlopidine, clopidogrel, and prasugrel), and direct P2Y12 inhibitors (ticagrelor, cangrelor and elinogrel). Of these, clopidogrel is the most commonly prescribed P2Y12 blocker; however, this product does not fulfill the ideal therapeutic requirements. The main limitations of clopidogrel administration include slow onset, prevention of recovery of platelet functions, and interindividual variability. Hence, advanced studies have been carried out to achieve more efficient and safer P2Y12 blockade. In this review, we provide a brief but comprehensive report on P2Y12, its role on platelet thrombus formation, and the targeting of this receptor as an intervention for cardiovascular disease, for the benefit of basic science and clinical researchers.