Platelet adhesion and aggregation at the site of coronary stenting can have catastrophic clinical and economic consequences. Therefore, effective platelet inhibition is vital during and after percutaneous coronary intervention. Eptifibatide is an intravenous antiplatelet agent that blocks the final common pathway of platelet aggregation and thrombus formation by binding to glycoprotein IIb/IIIa receptors on the surface of platelets. In clinical studies, eptifibatide was associated with a significant reduction of mortality, myocardial infarction, or target vessel revascularization in patients with acute coronary syndrome undergoing percutaneous coronary intervention. However, recent trials conducted in the era of dual antiplatelet therapy and newer anticoagulants failed to demonstrate similar results. The previously seen favorable benefit of eptifibatide was mainly offset by the increased risk of bleeding. Current American College of Cardiology/American Heart Association guidelines recommend its use as an adjunct in high-risk patients who are undergoing percutaneous coronary intervention with traditional anticoagulants (heparin or enoxaparin), who are not otherwise at high risk of bleeding. In patients receiving bivalirudin (a newer safer anticoagulant), routine use of eptifibatide is discouraged except in select situations (eg, angiographic complications). Although older pharmacoeconomic studies favor eptifibatide, in the current era of P2Y12 inhibitors and newer safer anticoagulants, the increased costs associated with bleeding make the routine use of eptifibatide an economically nonviable option. The cost-effectiveness of eptifibatide with the use of strategies that decrease the bleeding risk (eg, transradial access) is unknown. This review provides an overview of key clinical and economic studies of eptifibatide well into the current era of potent antiplatelet agents, novel safer anticoagulants, and contemporary percutaneous coronary intervention.