Schematic representation of the broad reach of plasminogen and the plasminogen activating system. The conventional function of this system has been in the removal of fibrin deposits and blood clots. Fibrin fibers formed following activation of coagulation are crossed linked by factor XIII (FXIII) and subsequently removed by plasmin. Activation of plasminogen by t-PA or u-PA can be inhibited by PAI-1 or PAI-2. Plasmin generation or activity can also be regulated by endogenous inhibitors: α2-antiplasmin (AP), TAFI, α2-macroglobulin (A2M), CI-inhibitor (C1-inh), or therapeutically by tranexamic acid (TXA), ε amino caproic acid (EACA; also a lysine analog), or aprotinin. Direct plasmin inhibitors are shown in red (AP, A2M, C1-inh, aprotinin), whereas those that inhibit plasmin generation (TAFI, TXA, EACA) are shown in blue. Plasminogen influences numerous other “additional” processes, some occurring via binding to plasminogen receptors (Plg-Rs) located on most leukocytes, permitting localized plasmin generation. Recent evidence has suggested that blocking plasmin formation might reduce viral infection and inflammation and improve immune function. On the other hand, plasminogen supplementation could be considered to improve wound healing, to more effectively remove parenchymal fibrin deposits, and to improve stroke thrombolysis. Plasminogen receptor blockade has also been proposed as a novel approach for malignant conditions.