The platelet ADP receptor antagonist clopidogrel is recommended for the treatment of patients with acute coronary syndrome and/or percutaneous coronary intervention. Patients who received a coronary stent in particular should be protected by sufficient antiplatelet therapy to prevent stent thrombosis. Clopidogrel is a prodrug and has to undergo extensive metabolization before the active metabolite can irreversibly bind to platelets. This makes clopidogrel treatment susceptible to genetic and drug interactions. Recent study findings suggest that initial treatment with a higher dose of clopidogrel may be superior to the currently approved dose. It is not clear whether this approach will be sufficient to entirely overcome clopidogrel hyporesponsiveness, which worsens outcomes in up to one-third of patients. Newer antiplatelet agents are emerging but clopidogrel remains the best established treatment option, with more than 120,000 patients treated in randomized trials and 12 years of clinical postmarketing experience.