Fibrinolysis serves an important role in the process of coagulation, ensuring that clots that are formed in response to injury resolve after the injured tissue is repaired. Fibrinolysis occurs because the protein plasminogen is converted to the active serine protease plasmin by its activating molecules (primarily tissue plasminogen activator). One of the inhibitors of fibrinolysis is alpha(2)-antiplasmin, which acts as the primary inhibitor of plasmin(ogen). Congenital deficiency of alpha(2)-antiplasmin causes a rare bleeding disorder because of increased fibrinolysis. Despite the rare nature of this disorder, understanding of the actions of alpha(2)-antiplasmin and the results of its deficiency has provided the opportunity for better understanding of the fibrinolytic system in both how it affects the risk of bleeding and its impact on other bodily systems. Here, we review the history of the discovery of alpha(2)-antiplasmin, our understanding of its genetics and function, and our current knowledge of its congenital deficiency. We also discuss some of the current avenues of investigation into its impact on other diseases and physiological states.