Cardiopulmonary bypass (CPB) activates and disrupts the hemostatic and inflammatory systems, which, in turn, makes an impact on the clinical outcome of patients. Postoperative bleeding is one common complication of CPB. Many techniques have been used to reduce post-operative bleeding, and pharmacological agents have demonstrated the greatest efficacy. In particular, the serine protease inhibitor, aprotinin, consistently reduces post-operative bleeding. The hemostatic mechanism of action of aprotinin; however, remains to be elucidated fully. The purpose of this review is to discuss the probable mechanisms of aprotinin action from the perspective of its interactions within the hemostatic and inflammatory pathways.