Pharmacologic manipulation of hemostasis is a prerequisite for cardiac surgery with cardiopulmonary bypass (CPB) to prevent clot formation in the extracorporeal circuit. Children who require surgical correction of congenital heart defects are at increased risk for prolonged and excessive bleeding after separation from CPB. Heparin remains the anticoagulant of choice for surgery requiring CPB. Traditional regimens of empiric heparin dosing and a fixed-dose ratio of protamine to heparin for reversal of anticoagulation do not account for individual differences in the half-life of heparin, clearance of heparin, and duration of CPB, particularly in children. In addition, the use of prolongation of the activated clotting time (ACT) as a measure of adequate anticoagulation does not account for alterations in ACT by factors unrelated to heparin activity, including hemodilution and hypothermia, that are frequently present during CPB. This manuscript reviews the pitfalls in the management of anticoagulation for children undergoing surgery that requires CPB. Pertinent literature related to the use of aprotinin, a serine protease inhibitor that has been shown to improve hemostasis during and after CPB, is discussed. It is hoped that this article will provide a practical guideline for the rational management of anticoagulation in children with congenital heart disease undergoing CPB surgery.