Perioperative myocardial infarction is a serious complication affecting a significant portion of patients undergoing coronary artery bypass graft surgery. This may arise due to coronary graft thrombosis, a rare but potentially fatal phenomenon associated with both congenital and acquired risk factors. Multiple case reports implicate the role of protamine in the development of such thromboses. The role of protamine in facilitating the regulation of hemostasis by reversing the anticoagulant effects of heparin in patients undergoing cardiopulmonary bypass is well-recognized. However, discussion of its potential contribution to coronary graft thrombosis and mechanisms by which this may occur is lacking. Furthermore, its narrow therapeutic index and side effect profile are such that its appropriateness as a universal reversal agent to heparin requires reconsideration. This article reviews the current body of evidence regarding the use of protamine in cardiac surgery and the limited case reports pertaining to its potential role in the pathophysiology of coronary graft thrombosis.