The last decade has seen the evaluation of several new oral anticoagulants that directly target thrombin or activated factor X (FXa). All demonstrate a rapid onset of action, a low potential for food and drug interactions, and a predictable anticoagulant effect that obviates the need for routine coagulation monitoring. Those agents at the most advanced stages of clinical development are a direct thrombin inhibitor, dabigatran, and direct FXa inhibitors, rivaroxaban and apixaban. Dabigatran and rivaroxaban are approved in more than 70 countries for prevention of venous thromboembolism in patients undergoing elective hip or knee arthroplasty, and apixaban is being considered for approval by regulatory agencies for this indication. Dabigatran was shown in a large phase III trial to be more effective and safer than warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation and has recently been approved for this indication. Edoxaban, an oral FXa inhibitor, is also being evaluated in phase III clinical trials. This review summarizes the pharmacology, clinical trial results, and future role of the new oral anticoagulants in clinical practice.