The heparin-protamine interaction is a topic of intense scrutiny due to its mandatory use during cardiopulmonary bypass. It can be estimated that over 2,000,000 patients are exposed to the heparin-protamine interaction each year. From clinical and experimental observation it is known that protamine neutralization of heparin causes increased pulmonary artery pressures and decreased systolic and diastolic blood pressure, myocardial oxygen consumption, cardiac output, heart rate, and systemic vascular resistance. These multiple cardiovascular effects are mediated via complement activation, histamine release, thromboxane and nitric oxide production, and antibody formation. This article reviews the current understanding of the heparin-protamine interaction from the world's literature.