Antiplatelet agents play a major role in patients undergoing percutaneous coronary intervention (PCI). Stent thrombosis and the demand for improved clinical outcomes have driven the need for aggressive antiplatelet and anticoagulant regimens and newer, more efficacious, therapies. The benefits of intravenous glycoprotein (GP) IIb/IIIa antagonists and clopidogrel in high-risk patients undergoing PCI appear complementary. In low- to intermediate-risk patients, clopidogrel pre-treatment and a maintenance dose of aspirin + clopidogrel for at least 1 year after PCI are supported by the data, although the optimal duration of clopidogrel treatment beyond 1 year remains hotly contested. The next generation of clinical trials will examine the benefits of antiplatelet and antithrombotic agents as adjunctive therapy with drug-eluting stents. A better understanding of our patients' overall risk will add to procedural success and more durable outcomes.