Surgical replacement of a native valve with a biological or mechanical prosthesis is the definitive treatment for many forms of advanced valvular heart disease. Mechanical heart valves are less prone to structural deterioration compared with bioprostheses, but require chronic oral anticoagulation to prevent thromboembolic events. Thromboembolic risk varies based on patient-related risk factors, including atrial fibrillation, advanced age, low ejection fraction, and hypercoagulability. Other important correlates of high thromboembolic risk include valve design, valve position, anticoagulation variability, and time from surgery. Clinical management is further complicated when antithrombotics may need to be interrupted or altered during surgery or pregnancy. At present, vitamin K antagonists are the only approved agents for thromboprophylaxis but are limited because of a narrow therapeutic window and requirement for frequent monitoring. Novel anticoagulants, including inhibitors of factor IIa and Xa, are currently being evaluated and may emerge as alternatives to vitamin K antagonists.