Glycoprotein IIb/IIIa inhibitors (GPIs) represent a cornerstone in the evolution of antiplatelet therapy, initially developed from insights into Glanzmann thrombasthenia. These agents include abciximab, eptifibatide, tirofiban, and the investigational agent zalunfiban. They act by inhibiting the final common pathway of platelet aggregation. Although once routinely used during percutaneous coronary intervention (PCI), the emergence of potent oral P2Y inhibitors has led to their selective use, primarily in high thrombotic risk or bailout situations. This review explores the history, mechanism of action, pharmacologic properties, and clinical applications of GPIs in coronary and noncoronary interventions. Current clinical guidelines limit their use to specific indications, emphasizing individualized risk and benefit assessment. Zalunfiban, a novel subcutaneous agent, is under clinical investigation for prehospital management of ST-elevation myocardial infarction. While GPIs remain relevant in select settings such as acute limb ischemia, neurointerventions, and perioperative bridging, their overall role continues to evolve in the context of modern antiplatelet therapy.