Aprotinin is a naturally occurring serine protease inhibitor that is being used with increasing frequency in cardiac surgery and beyond to reduce blood loss and the need for perioperative blood transfusion. Through inhibition of serine proteases such as plasmin, aprotinin significantly reduces fibrinolysis, thereby aiding hemostasis during surgical procedures. In addition, aprotinin interacts with other factors in the coagulation and fibrinolytic cascade, creating a hemostatic balance, without increasing the risk of thrombosis. These proven benefits are supplemented by the anti-inflammatory properties of aprotinin, which may help curb some of the deleterious effects of cardiopulmonary bypass. This article will review the discovery of aprotinin, its mechanism of action, dosing and adverse effects, and highlight the major recent trials demonstrating its efficacy.