Protamine, a highly basic protein isolated from salmon sperm, is the only clinically available agent to reverse the anticoagulation of unfractionated heparin. Following intravenous administration, protamine binds to heparin in a nonspecific electrostatic interaction to reverse its anticoagulant effects. In clinical use, protamine is routinely administered to reverse high-dose heparin anticoagulation in cardiovascular procedures, including cardiac surgery with cardiopulmonary bypass. Despite the lack of supportive evidence regarding protamine’s effectiveness to reverse low-molecular-weight heparin, it is recommended in guidelines with low-quality evidence. Different dosing strategies have been reported for reversing heparin in cardiac surgical patients based on empiric dosing, pharmacokinetics, or point-of-care measurements of heparin levels. Protamine administration is associated with a spectrum of adverse reactions that range from vasodilation to life-threatening cardiopulmonary dysfunction and shock. The life-threatening responses appear to be hypersensitivity reactions due to immunoglobulin E and/or immunoglobulin G antibodies. However, protamine and heparin-protamine complexes can activate complement inflammatory pathways and inhibit other coagulation factors. Although alternative agents for reversing heparin are not currently available for clinical use, additional research continues evaluating novel therapeutic approaches.