INTRODUCTION: Ischemic stroke (IS) is a major cause of death and disability worldwide. The P2Y12 receptor plays a critical role in the formation of a stable thrombus leading to ischemic complications. Therefore, P2Y12 receptor inhibitors constitute a major antiplatelet strategy in the secondary prevention of IS. AREAS COVERED: We searched articles about P2Y12 receptor inhibitors and stroke in PubMed published until December 2014. This is a comprehensive review of the role of P2Y12 receptor inhibitors alone and in combination with aspirin in the secondary prevention of noncardioembolic stroke. EXPERT OPINION: The potential benefit of more potent antiplatelet therapy for secondary stroke prevention must be weighed against the risk of bleeding in patients with IS. Short-term (≤ 3 months) dual antiplatelet therapy with clopidogrel and aspirin that is initiated early after IS or transient ischemic attack due to large artery atherosclerosis appears most efficient.