Many advances have occurred in the pharmacological treatment of venous thromboembolism (VTE) since the vitamin K antagonists (eg, warfarin) and unfractionated heparin were introduced over 60 years ago, but warfarin and other coumarin derivatives remain the only orally administered anticoagulants available for long-term prevention and treatment of VTE. The coumarin derivatives are not convenient to use, as they have a narrow therapeutic index and require frequent laboratory monitoring and dosage adjustment. The low-molecular-weight heparins, and the indirect factor Xa inhibitor, fondaparinux, offer improvements, but both agents still need to be administered subcutaneously. A number of new, orally available, direct inhibitors of factor Xa or thrombin are in development and offer ease of use and predictability of dosing so that monitoring is not required. These agents hold great promise as new anticoagulants that might provide greater efficacy and safety, and because of these attributes, might lead to greater use of anticoagulant therapy for patients not currently treated.