Cardiovascular disease is associated with a heightened risk of thrombosis that can manifest as acute myocardial infarction, cardiac death, and stroke. Similarly, valvular heart disease (which alters blood-flow dynamics) and the insertion of prosthetic materials (which stimulates localized thrombosis on foreign surfaces) are associated with platelet aggregation and thrombin-mediated bioamplification of the coagulation cascade. Physiologic principles and pathobiologic mechanisms determine the preferred means either to prevent or attenuate both thrombosis and subsequent cardiovascular events. Anticoagulant therapy in hospital- and outpatient-based settings has appropriately assumed a central role in the prevention and treatment of thrombotic disorders of the cardiovascular system. Carefully-designed clinical trials will establish safe and effective antithrombotic therapies for wide-scale implementation.