Venous thromboembolism (VTE) is a major health problem. Anticoagulation can significantly decrease the morbidity and mortality associated with VTE. Heparin and coumarin derivatives have been the standard of care for the last 50 years, and the development of low-molecular-weight heparin preparations has significantly improved the prevention and treatment of venous thromboembolic disease. With these advances, investigators are now able to address some of the unresolved issues in antithrombotic therapy, including the search for the optimal antithrombotic agent in high-risk patients, the optimal timing of thromboprophylaxis initiation in the surgical population, and the duration of prophylaxis for the prevention of initial and recurrent VTE events. Clinical trials have begun to investigate many of these issues, and the resulting data have already contributed to improving the management of patients with a high risk of VTE.