Platelet-dependent thrombosis plays a central role in the pathophysiology of myonecrosis in both percutaneous coronary interventions (PCIs) and acute coronary syndromes (ACS). Extensive data from randomized clinical trials support the use of acute therapies that interfere with platelet aggregation to provide clinical benefit to patients presenting with ACS and undergoing PCI. Glycoprotein (GP) IIb/IIIa receptor antagonists represent a major advance in the therapy of patients undergoing PCI and those with non-ST segment elevation (NSTE) ACS. Eptifibatide, a small molecule GP IIb/IIIa receptor antagonist, is one such agent. A more consistent platelet-inhibitory effect over time and the short half-life of eptifibatide represent potential pharmacologic advantages compared with other drugs within this class. Large, randomized clinical trials have demonstrated the benefits of eptifibatide for treating patients with NSTE ACS and patients undergoing PCI, establishing its central role in modern management of these conditions. However, recent new advances in the pharmacotherapy of ACS and PCI are requiring us to reconsider the role of GP IIb/IIIa inhibitors; therefore, ongoing and future randomized clinical trials will re-examine GP IIb/IIIa inhibition and establish the role of GP IIb/IIIa inhibitors for the next decade.