The P2Y₁₂ antagonist clopidogrel has a well-established role as an antithrombotic agent in the settings of percutaneous coronary intervention and acute coronary syndromes. However, several challenges remain, including the relatively slow onset of action of clopidogrel and the phenomenon of clopidogrel response variability or “resistance”. Novel P2Y₁₂ antagonists, including prasugrel, AZD6140, and cangrelor, have a faster onset of action, as well as more potent, and less variable, inhibition of platelet function ex vivo. Whether this promise will be translated into clinical benefit for patients will be determined by the results of ongoing phase 3 clinical trials.