Adenosine diphosphate plays a key role in platelet activation related to arterial thrombosis, mainly through interaction with P2Y12 receptors. Accordingly, P2Y12 receptor inhibitors have been developed to prevent ischemic events. Currently, available agents include thienopyridines, namely ticlopidine, clopidogrel, and prasugrel, and non-thienopyridines, including ticagrelor and cangrelor. Thienopyridines are oral pro-drugs that need hepatic conversion into active metabolites to exert their antiplatelet effects by irreversible binding to the P2Y12 receptor. Ticlopidine was the first agent available for clinical use but showed an unfavorable safety profile that led to the development of clopidogrel, a second-generation thienopyridine, showing similar antiplatelet properties but with a more favorable safety profile. However, the pharmacodynamic effects of clopidogrel are characterized by high interindividual variability. Prasugrel is a third-generation thienopyridine with a more efficient pharmacokinetic profile translating into more potent and less variable pharmacodynamic effects compared with clopidogrel. Non-thienopyridine agents are direct-acting, thus not requiring hepatic conversion, and are characterized by reversible binding to the P2Y12 receptor. Ticagrelor is an orally available P2Y12 receptor antagonist that shows similar potency compared to prasugrel but requires twice-daily dosing. Cangrelor is the only intravenously available P2Y12 receptor antagonist, characterized by prompt and potent platelet inhibitory effects but also a very fast offset of action due to its short half-life. The field of P2Y12 receptor antagonists continues to expand, with two new drugs, vicagrel, and selatogrel currently under development. Vicagrel is a novel thienopyridine that is converted into the same active metabolites as clopidogrel, while selatogrel can be administered subcutaneously, being currently investigated for self-administration.