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, clopidogrel has a number of disadvantages that have led to the development of new P2Y12 antagonists. This article reviews the current status of clopidogrel and these new P2Y12 antagonists.A poor response to clopidogrel as measured by in-vitro platelet function assays is associated with a poor clinical response to clopidogrel. A patient's response to clopidogrel is partly dependent on factors that decrease (reduced-function CYP2C19 allele; omeprazole) or increase (cigarette smoking) the metabolism of clopidogrel through cytochrome P450 in the liver. Novel P2Y12 antagonists (prasugrel, ticagrelor, cangrelor, and elinogrel) that have advantages over clopidogrel - including more rapid, less variable, and more complete inhibition of platelet function - are in various phases of development.The clinical benefit of changing clopidogrel treatment based on platelet function tests, single-nucleotide polymorphisms, or both is as yet unproven. Novel P2Y12 antagonists are under investigation to determine whether they can result in better, more rapid, or both, antithrombotic effects than clopidogrel, without an unacceptable increase in hemorrhagic or other side effects.