As the pathophysiology of acute coronary syndromes (ACS) has been clarified in recent years, major advances have been made in the management of the disease. The magnitude of the thrombotic process triggered upon plaque disruption is modulated by different elements that determine plaque and blood thrombogenicity. Thrombin plays a pivotal role in ACS because of its extensive procoagulant and prothrombotic actions. Antithrombotic therapy and powerful antiplatelet therapies, in addition to early percutaneous coronary intervention (PCI), have become central in the management of ACS. A number of options for anticoagulation regimens are available. However, many agents currently used have significant limitations, recognition of which has led to the development, evaluation and clinical introduction of the class of thrombin-specific anticoagulant agents. This paper will discuss the clinical development of the direct thrombin inhibitor bivalirudin as the core anticoagulant in the contemporary PCI setting and the implications for its use in ACS.