This article concerning the pharmacokinetics and pharmacodynamics of vitamin K antagonists (VKAs) is part of the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. The article describes the antithrombotic effect of VKAs, the monitoring of anticoagulation intensity, the clinical applications of VKA therapy, and the optimal therapeutic range of VKAs, and provides specific management recommendations. Grade 1 recommendations are strong, and indicate that the benefits do, or do not, outweigh the risks, burdens, and costs. Grade 2 suggests that individual patient’s values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S–187S). Among the key recommendations in this article are the following: for dosing of VKAs, we suggest the initiation of oral anticoagulation therapy with doses between 5 and 10 mg for the first 1 or 2 days for most individuals, with subsequent dosing based on the international normalized ratio (INR) response (Grade 2B). In the elderly and in other patient subgroups with an elevated bleeding risk, we suggest a starting dose at ≤ 5 mg (Grade 2C). We recommend basing subsequent doses after the initial two or three doses on the results of INR monitoring (Grade 1C). The article also includes several specific recommendations for the management of patients with INRs above the therapeutic range and for patients requiring invasive procedures. For example, in patients with mild to moderately elevated INRs without major bleeding, we suggest that when vitamin K is to be given it be administered orally rather than subcutaneously (Grade 1A). For the management of patients with a low risk of thromboembolism, we suggest stopping warfarin therapy approximately 4 days before they undergo surgery (Grade 2C). For patients with a high risk of thromboembolism, we suggest stopping warfarin therapy approximately 4 days before surgery, to allow the INR to return to normal, and beginning therapy with full-dose unfractionated heparin or full-dose low-molecular-weight heparin as the INR falls (Grade 2C). In patients undergoing dental procedures, we suggest the use of tranexamic acid mouthwash (Grade 2B) or epsilon amino caproic acid mouthwash without interrupting anticoagulant therapy (Grade 2B) if there is a concern for local bleeding. For most patients who have a lupus inhibitor, we suggest a therapeutic target INR of 2.5 (range, 2.0 to 3.0) [Grade 2B]. In patients with recurrent thromboembolic events with a therapeutic INR or other additional risk factors, we suggest a target INR of 3.0 (range, 2.5 to 3.5) [Grade 2C]. As models of anticoagulation monitoring and management, we recommend that clinicians incorporate patient education, systematic INR testing, tracking, and follow-up, and good communication with patients concerning results and dosing decisions (Grade 1C+).