Direct thrombin inhibitors (DTIs) are a new class of therapeutics possessing theoretic advantages over unfractionated heparin (UFH). In contrast to UFH, DTIs do not activate platelets, have no circulating inhibitors, and bind to both free and clot-bound thrombin. These theoretical advantages have spurred clinical trials investigating DTIs in a variety of cardiovascular indications. Currently, the major role for DTIs in cardiology is as an adjunct during percutaneous coronary intervention (PCI). Such a role stems from the results of the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 randomized trial, in which bivalirudin with provisional abciximab was demonstrated to be equivalent to UFH plus planned abciximab with respect to ischemic endpoints, while being associated with less bleeding. Ongoing clinical trials will define the role of bivalirudin as an adjunct to primary PCI for ST-segment elevation myocardial infarction and in non-ST segment elevation acute coronary syndrome as an adjunct to an early invasive strategy.