Although heparin has been a cornerstone of treatment for the prevention of thrombosis, it is limited by its adverse effects and unpredictable bioavailability. Direct thrombin inhibitors are a novel class of drugs that have been developed as an effective alternative mode of anticoagulation in patients who suffer from heparin-induced thrombocytopaenia, and for the management of thromboembolic disorders and acute coronary syndromes. The main disadvantages of the direct thrombin inhibitors are the lack of an antidote or readily available clinical monitoring. The mechanism of action, the properties of direct thrombin inhibitors and their potential to replace currently available anticoagulants are reviewed.