Tissue-type plasminogen activator (t-PA) is most likely synthesized by the endothelia of the circulatory tract where it comes into contact with the blood. Subnormal levels of t-PA activity have in numerous reports been found associated with thrombotic tendencies. This chapter describes the protein components involved in t-PA mediated fibrinolysis and how these proteins interact. Several different stimuli are known to induce release of t-PA from the endothelial cells: exercise, venous occlusion, mental stress, and/or administration of vasopressin analogue. Fast-acting inhibitory activity is neutralized by released t-PA, and hence may enhance the fibrinolytic activity of the blood to prevent thrombosis. A protease inhibitor that reacts rapidly with single-chain t-PA has been identified in cell culture medium and, more recently, in blood plasma. Fibrin in the form of a clot is known to be t-PA stimulatory since the early and mid 1970s.