The coagulation and fibrinolytic systems safeguard the patency of the vasculature and surrounding tissue. Cross regulation of coagulation and fibrinolysis plays an important role in preserving a balanced hemostatic process. Identification of Thrombin Activatable Fibrinolysis Inhibitor (TAFI) as an inhibitor of fibrinolysis and one of the main intermediates between coagulation and fibrinolysis, greatly improved our understanding of cross regulation of coagulation and fibrinolysis. As TAFI is an enzyme that is activated by thrombin generated by the coagulation system, its activation is sensitive to the dynamics of the coagulation system. Defects in coagulation, such as in thrombosis or hemophilia, resonate in TAFI-mediated regulation of fibrinolysis and imply that clinical symptoms of coagulation defects are amplified by unbalanced fibrinolysis. Thrombomodulin promotes the generation of both antithrombotic activated protein C (APC) and prothrombotic (antifibrinolytic) activated TAFI, illustrating the paradoxical effects of thrombomodulin on the regulation of coagulation and fibrinolysis. This review will discuss the role of TAFI in the regulation of fibrinolysis and detail its regulation of activation and its potential therapeutic applications in thrombotic disease and bleeding disorders.