Abstract | Antiplatelet drugs, such as aspirin, P2Y12 antagonists, and glycoprotein (GP) IIb/IIIa inhibitors, have proved to be successful in reducing the morbidity and mortality associated with arterial thrombosis. These agents are, therefore, the cornerstone of therapy for patients with acute coronary syndromes. However, these drugs all carry an inherent risk of bleeding, which is associated with adverse cardiovascular outcomes and mortality. Thus, the potential benefits of more potent, conventional antiplatelet drugs are likely be offset by the increased risk of bleeding. Data from experiments in vivo have highlighted potentially important differences between haemostasis and thrombosis, raising the prospect of developing new antiplatelet drugs that are not associated with bleeding. Indeed, in preclinical studies, several novel antiplatelet therapies that seem to inhibit thrombosis while maintaining haemostasis have been identified. These agents include inhibitors of phosphatidylinositol 3-kinase-β (PI3Kβ), protein disulfide-isomerase, activated GPIIb/IIIa, GPIIb/IIIa outside-in signalling, protease—activated receptors, and platelet GPVI-mediated adhesion pathways. In this Review, we discuss how a therapeutic ceiling has been reached with existing antiplatelet drugs, whereby increased potency is offset by elevated bleeding risk. The latest advances in our understanding of thrombus formation have informed the development of new antiplatelet drugs that are potentially safer than currently available therapies.