Anticoagulants are widely used for the prevention and treatment of venous and arterial thrombosis. Current treatment strategies often employ a combination of parenteral and oral agents because the only available orally active anticoagulants, vitamin K antagonists, have a delayed onset of action.[ 1 ] Furthermore, vitamin K antagonists have a narrow therapeutic window that necessitates careful anticoagulation monitoring, and dosing is problematic because of multiple food and drug interactions. These limitations highlight the need for oral anticoagulants that produce a more predictable anticoagulant response than vitamin K antagonists, thereby obviating the need for laboratory monitoring. Ximelagatran has the potential to meet this need. A prodrug of melagatran, an agent that targets thrombin, ximelagatran exhibits many of the characteristics of an ideal anticoagulant. This article (1) reviews the limitations of vitamin K antagonists, (2) lists the characteristics of an ideal anticoagulant, (3) rationalizes thrombin as a target for new anticoagulants, (4) reviews the preclinical and clinical data with ximelagatran, and (5) provides clinical perspective as to the future of ximelagatran and other orally active anticoagulants currently under development.