In 2006, the American College of Cardiology, American Heart Association, and Society for Cardiovascular Interventions published the 2005 update of the evidence-based guidelines for the treatment of patients undergoing percutaneous coronary intervention (PCI). Together with procedural recommendations, these guidelines for percutaneous coronary intervention provide clinicians with guidance in the appropriate use of adjunctive pharmacologic therapy in patients undergoing PCI. However, there remain substantial variations in practice among clinicians and within and across institutions. Furthermore, the guidelines (being a static document) cannot incorporate additional evidence that has accumulated since their publication. Several landmark trials, notably Intracoronary Stenting and Antithrombotic Regimen—Rapid Early Action for Coronary Treatment (ISAR-REACT 2) and Acute Catheterization and Urgent Intervention Triage strategY (ACUITY), have added substantially to the knowledge base about pharmacologic therapy since publication of the guidelines. This article is therefore intended to discuss implementation into clinical practice of the revised guidelines for antiplatelet and antithrombotic pharmacologic therapy during PCI and to evaluate recent clinical evidence and make recommendations for revision of the guidelines incorporating the outcomes of recently completed trials.