Thrombus formation at a site of arterial injury (eg, rupture of an atherosclerotic plaque in a carotid artery), a crucial step in the pathogenesis of cerebral ischemia, is initiated by the adhesion of platelets to the arterial wall. In vivo, activated platelets release adenosine diphosphate (ADP), whose binding to the platelet P2Y12 receptor elicits progressive and sustained platelet aggregation. As a result, this receptor has been a target for the development of clinically effective antiplatelet agents, such as the thienopyridines ticlopidine and, more recently, clopidogrel, the only two currently FDA-approved P2Y12 antagonists. Clopidogrel has a well-established role as an antithrombotic agent in the setting of ischemic stroke. However, several challenges remain, including the relatively slow onset of action of this drug and the phenomenon of clopidogrel response variability or "resistance". A number of novel P2Y12 antagonists are therefore under investigation to determine whether they can result in better or more rapid antithrombotic effects than clopidogrel, without an unacceptable increase in hemorrhagic (or other) side effects. These include 1) prasugrel, an orally-administered thienopyridine prodrug, 2) ticagrelor (AZD6140), an ATP analog reversible P2Y12 antagonist, 3) cangrelor, an intravenously-administered reversible P2Y12 antagonist, and 4) PRT060128. Whether the promising pharmacological profile of these drugs will be translated into clinical benefit for stroke patients will be determined by the results of clinical trials.