Venous thromboembolism (VTE) is a common and potentially lethal disease that recurs frequently and is associated with long-term impairment and suffering. Despite a great deal of effort, the incidence of VTE has not changed substantially in the last 20 years. Independent risk factors include hospitalization (either for surgery or for acute medical illness), trauma, malignant neoplasm, central venous catheters or transvenous pacemakers, superficial vein thrombosis, and extremity paresis. Of these, hospitalization accounts for almost 60% of all VTE occurring in the community. Thus, universal effective prophylaxis of hospitalized patients would significantly reduce the incidence of VTE. Parenteral direct thrombin inhibitors are safe and effective for both prevention and treatment of acute VTE, and do not require laboratory monitoring or dose adjustment. Oral direct thrombin inhibitors may also be safe and effective, and offer enhanced convenience without diet or drug-drug interactions.