Complement activation and the resulting inflammatory response is an important potential mechanism for multisystem organ injury in cardiac surgery. Novel therapeutic strategies using complement inhibitors may hold promise for improving outcomes for cardiac surgical patients by attenuating complement activation or its biologically active effector molecules. Recent clinical trials evaluating complement inhibitors have provided important data to further delineate the impact of complement activation and its inhibition on clinical outcomes. In this review we examine the role of complement activation and its inhibition as a therapeutic approach in cardiac surgery.