The fibrinolytic system plays a vital role in maintaining vital organ homeostasis. Fibrinolysis, defined as the dissolution of fibrin (the major scaffold for intravascular thrombus), is the process that regulates thrombus growth after hemostasis has been achieved, thus preserving tissue perfusion. An understanding of fibrinolysis has led to the development of pharmacologic agents that can be used in the treatment of arterial and venous thrombotic disorders, including acute myocardial infarction, acute ischemic stroke, and pulmonary embolism. Fibrinolytic therapy makes use of the vascular system’s intrinsic defense mechanism by accelerating and amplifying the conversion of an inactive enzyme precursor (zymogen), plasminogen, to the active enzyme plasmin. In turn, plasmin hydrolyzes several key bonds in the fibrin (clot) matrix, causing dissolution (lysis). A single-chain glycoprotein consisting of 790 amino acids, plasminogen is converted to plasmin by cleavage of the Arg560–Val561 peptide bond. The plasminogen molecule also contains specific lysine binding sites, which mediate its interaction with fibrin and α2-plasmin inhibitor. A serine protease with trypsinlike activity, plasmin attacks lysyl and arginyl bonds of fibrin at two principal sites: (1) the carboxyterminal portion α-chain (polar region) and (2) the coiled coil connectors containing α-, β-, and γ-chains. The ability of a fibrinolytic agent to dissolve an occlusive thrombus is determined by several factors. After administration the agent must be delivered to, perfuse, and ultimately infiltrate the thrombus while concomitantly being provided with an adequate amount of substrate (plasminogen) and the appropriate metabolic environment for an enzymatic reaction (conversion of plasminogen to plasmin) to take place. The intrinsic composition or ultrastructure of a thrombus also affects its lysability. Changes in the total amount and distribution of blood flow determine oxygen delivery to metabolically active tissues. They also determine the delivery of enzymatic substrate and plasminogen activators to the occlusive thrombus. In the heart, coronary blood flow correlates directly with mean arterial pressure. The flow-pressure curve is relatively flat above 65 to 70 mmHg, but becomes steeper as the mean arterial pressure decreases below this point. The relationship within the brain is more complex.