Anticoagulation is required for successful implementation, maintenance, and separation from cardiopulmonary bypass (CPB). The coagulation, fibrinolytic, and inflammatory systems are all activated during CPB, and it is essential to understand the coagulation system and the interrelatedness of the intrinsic pathway, extrinsic pathway, and platelets to minimize the activation of the hemostatic system. Appropriate anticoagulant selection, dosing, monitoring, and maintenance are required to avoid catastrophic thrombosis and pump failure. While several novel anticoagulants have been developed in the past few decades, unfractionated heparin remains the anticoagulant used for CPB with monitoring using activated clotting time (ACT) and/or heparin concentration. For patients with heparin-induced thrombocytopenia/thrombosis (HITT), the use of unfractionated heparin (UFH) is limited. In such cases, alternative anticoagulation methods are necessary. Direct thrombin inhibitors like bivalirudin and argatroban are often used as substitutes. Additionally, platelet inhibitors may be considered to manage the risk of thrombosis without triggering HITT. These alternatives provide effective anticoagulation while minimizing the complications associated with UFH in sensitive patients. This chapter will comprehensively explore the various anticoagulation options available for effective anticoagulation management during CPB.