INTRODUCTION Thromboembolic events are significant sources of morbidity and mortality that often necessitate long-term anticoagulation therapy. Although a variety of effective anticoagulants exist, heparins, heparinoids, and most direct thrombin inhibitors are available as injectable formulations and are typically unsuitable for long-term use. Warfarin (Coumadin, Bristol-Myers Squibb), an oral vitamin K antagonist, has been the primary agent utilized in long-term anticoagulation therapy. Despite its ability to reduce and treat thromboembolic events, warfarin therapy has several limitations, including a slow onset of action; a narrow therapeutic range; variable patient responses; and numerous interactions with drugs, herbal medications, and foods containing vitamin K. As a result of this agent’s pharmacokinetic (PK) and pharmacodynamic (PD) limitations, patients receiving warfarin often require frequent monitoring to ensure optimal efficacy and safety. In recent years, efforts have been focused on the development of new oral anticoagulants with further predictable PK and PD profiles, which may reduce the need for vigilant monitoring. Thrombin has been identified as an essential target of therapy because of its pivotal role in the coagulation process. Thrombin is responsible for the conversion of soluble fibrinogen to fibrin; clot stabilization through activation of factor XIII and the formation of cross-linkage among fibrin molecules; and the generation of additional thrombin through activation of factors V, VIII, and XI. Direct thrombin inhibitors (DTIs) are an innovative class of anticoagulants that bind directly to thrombin to inhibit its actions and impede the clotting process. Although clinically available DTIs are parenteral agents, efforts are being concentrated in the development of an oral DTI. Ximelagatran (Exanta, AstraZeneca) was a promising oral DTI that had been studied in numerous clinical trials and received approval for venous thromboembolism prophylaxis in Europe. However, in data submitted to the U.S. Food and Drug Administration (FDA), liver enzyme elevations were observed in patients receiving prolonged therapy for more than 35 days. Based on central and local laboratory data, the incidence of alanine aminotransferase (ALT) levels greater than three times the upper limit of normal (ULN) was 7.9% for the ximelagatran group and 1.2% for the comparators. The incidence of ALT levels greater than five times the ULN was 4.7% and 0.5% in the ximelagatran and comparator groups, respectively, and the incidence of ALT levels greater than 10 times the ULN was 1.9% and less than 0.1%, respectively. Aspartate aminotransferase (AST) levels also increased in conjunction with ALT levels. As a result of these safety concerns, an FDA advisory committee recommended against the approval of ximelagatran in the U.S. In 2006, AstraZeneca announced its decision to withdraw ximelagatran from the market and to terminate its development. Dabigatran etexilate (Rendix, Boehringer Ingelheim) is a new oral DTI that is currently being studied in clinical trials. Several phase 2 studies have been completed with encouraging results, and recruitment is being conducted for several phase 3 studies. This article presents a review of the currently available information on this investigational product.