Because of the central role of platelets in cardiovascular atherothrombosis, there is a well-established therapeutic role for antiplatelet therapy that includes aspirin (a cyclooxygenase 1 [COX1] inhibitor), clopidogrel (an antagonist of the ADP P2Y(12) receptor), and the GPIIb-GPIIIa (αIIbβ3) antagonists. However, there remains a significant incidence of arterial thrombosis in patients treated with currently available antiplatelet therapy. Novel P2Y(12) antagonists such as the recently US Food and Drug Administration (FDA)-approved prasugrel, along with ticagrelor, cangrelor, and elinogrel, have advantages over clopidogrel, including more rapid, less variable, and more complete inhibition of platelet function. Currently ongoing phase 3 studies will determine whether these new P2Y(12) antagonists will result in better and/or more rapid antithrombotic effects than clopidogrel, without an unacceptable increase in hemorrhagic or other side effects, as has been recently reported in some clinical settings for prasugrel and ticagrelor. Antagonists of the thrombin receptor protease-activated receptor 1 (PAR1) are also undergoing phase 3 trials, and many other novel antiplatelet agents are under investigation as antithrombotic agents.