The interaction of ADP with its platelet receptor P2Y12 plays a crucial role in platelet activation and thrombogenesis. This article reviews the pharmacology and clinical trials of specific antagonists of P2Y12. Clopidogrel is a thienopyridine with proven antithrombotic efficacy, but it has some important drawbacks: i) it is a pro-drug that needs to be metabolized to its active metabolite; ii) it has a delayed onset and offset of action; iii) there is high inter-individual variability in pharmacological response. Prasugrel is also a thienopyridine, with faster onset of action and more uniform inhibition of platelet function compared to clopidogrel, accounting for lower incidence of ischemic events in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) and higher incidence of both non-CABG (Coronary Artery Bypass Grafting) related bleeding complications. Two direct and reversible P2Y12 antagonists, cangrelor and ticagrelor, are characterized by rapid onset and reversal of platelet inhibition. Cangrelor did not prove superior to clopidogrel in preventing thrombotic events in patients undergoing PCI. Ticagrelor proved to be superior to clopidogrel in preventing major adverse cardiac events in ACS patients, but was, like prasugrel, was associated with higher frequency of non-CABG-related bleeding complications. A shorter period of drug discontinuation before surgery was necessary in ticagrelor-treated patients compared to clopidogrel-treated patients to limit the severity of post-surgical bleeding.