To develop a rational approach to antithrombotic therapy, in cardiac disease, a sound understanding is required (1) of the hemostatic processes leading to thrombosis, (2) of the various antithrombotic agents, and (3) of the relative risks of thrombosis and thromboembolism in the various cardiac disease entities. With the understanding of pathogenesis and risk of thrombus formation, a rational approach to the use of antiplatelet and anticoagulant agents can be formulated. Those at high risk of thrombus formation should generally receive a high degree of antithrombotics and, depending on the pathophysiology of the thrombus, may benefit from the concomitant use of antiplatelet and anticoagulant agents. Those with a medium risk of thrombus formation may benefit with the use of an antiplatelet agent alone or anticoagulants alone. Patients at low risk of thrombus formation should not receive antithrombotics. Such rational approach to antithrombotic therapy serves as the basis of this article.