This review examines the role of platelets in ischemic stroke, platelet activation mechanisms, aspirin's rise as an antithrombotic agent, clopidogrel's appearance on the stage, a possible role for combination therapy, antiplatelet resistance, practical considerations, and future directions. Reviewed in this chapter are issues central to optimal antiplatelet therapy: efficacy, safety, resistance, and biochemical/laboratory testing. Current guidelines do not recommend combination aspirin and clopidogrel use, however recent research indicates dual antiplatelet therapy with combined aspirin and clopidogrel may have specific roles in secondary prevention of ischemic stroke. A cautious and analytical interpretation of the literature is advised before application of this knowledge to clinical practice. The best recommendation at this time is to follow the published guidelines for secondary prevention of ischemic stroke.