Thrombin is a pivotal enzyme in the coagulation cascade and in the pathogenesis of thrombosis, which can lead to the occurrence of a number of coronary syndromes. Thrombin inhibition, by either recombinant or synthetic inhibitors, has now been recognised as a possible mechanism by which to modulate thrombosis; a cause of considerable mortality and morbidity, particularly in the western world. This approach represents a departure from established antithrombotic therapy, the mainstay therapies for which are aspirin, heparin or warfarin. There is now a body of clinical evidence with recombinant peptide or protein based thrombin inhibitors, and, to a lesser extent, synthetic agents, which give useful insights into the potential therapeutic impact of direct thrombin inhibitors. As well as defining the key clinical parameters where these drugs can be beneficial, clinical studies have also highlighted specific areas which need to be addressed by newer compounds in this class. A number of examples of low molecular weight and potentially orally available compounds are now in early clinical development; they may serve to answer many of the questions raised by Phase III trials with compounds based on hirudin.