Thromboembolic diseases are a major health problem and one of the most preventable causes of morbidity and mortality in hospitalized patients. Heparins and the vitamin K antagonists (VKAs) have been the mainstay of therapy for > 60 years.1 Both classes of agents, however, have limitations. The heparins must be administered parenterally and are associated with thrombocytopenia and, with long-term use, osteopenia. VKAs have the disadvantages of slow onset, prolonged effect, and a narrow therapeutic window, with multiple food and drug interactions that require frequent monitoring.1 In addition, metabolism of VKAs is altered by genetic factors that affect dosing and efficacy.2 The “ideal” anticoagulant should be as effective and safe as heparin and VKAs but should also be available in both a parenteral and an oral formulation, rapidly acting, with excellent bioavailability. It should have low protein binding and rapid elimination. It should be free of significant food or drug interactions, leading to a predictable effect and a wide therapeutic window with no need for close monitoring. In addition, it should lack significant toxicities unrelated to the anticoagulant activity. It should target a specific free and clot-bound coagulation factor and have a specific antidote should rapid reversal be necessary. Finally, it should be cost effective.1,3 There are now agents that fulfill some of these criteria. These include agents that target activated factor X and agents that directly inhibit thrombin. This review focuses on the oral activated factor X inhibitors rivaroxaban and apixaban and the oral direct thrombin inhibitor dabigatran, as they have undergone the most extensive phase 3 testing and are currently approved for use for select indications in the United States, Canada, or Europe.