Because of the central role of platelets in mediating ischemic events, antiplatelet agents are critical components of atherothrombosis prevention. Given their robust safety and efficacy profiles, aspirin and clopidogrel are consistently recommended by evidence-based treatment guidelines. Despite these recommendations, controversies surrounding the appropriate application of aspirin and clopidogrel remain. Questions of appropriate dosing, length of therapy, and use of combination therapy are most pressing, and considerable debate exists regarding the variability of response to antiplatelet therapy, including the definition, measurement, and clinical relevance of responsiveness. This review discusses the facts and controversies surrounding the use of aspirin and clopidogrel. Overall, despite the existing controversies, antiplatelet therapy with aspirin and/or clopidogrel remains a proven and essential therapeutic tool for safe and effective management of atherothrombotic risk in specific clinical settings.