Antiplatelet therapy is a cornerstone in the management of acute coronary syndromes. Clopidogrel produces irreversible inhibition of the platelet adenosine diphosphate receptor, thereby attenuating activation and aggregation of platelets. Clopidogrel has been shown to prevent stent thrombosis in patients undergoing percutaneous coronary intervention (PCI) and reduces major adverse cardiovascular events in patients with unstable angina or non-ST-segment elevation myocardial infarction (non-STEMI). Recent studies have left clinicians with many questions regarding the role and dosing regimens of clopidogrel in STEMI, PCI, and primary or secondary prevention. Based on an analysis of the data, clopidogrel should be given in addition to aspirin and fibrinolytic therapy to patients with STEMI. In patients undergoing PCI, a loading dose of clopidogrel 600 mg should be given if the procedure needs to be performed within 15 hours of initial presentation. If PCI can be delayed for 15 hours or more, a loading dose of 300 mg can be used. Evidence also suggests that clopidogrel should not be prescribed for primary prevention in high-risk patients.