Transport of fibrinolytic agents into thrombi represents a rate limiting step in therapeutic thrombolysis. Mathematical modeling predicts and in vitro experiments demonstrate that effective delivery of fibrinolytic agents into clots is the most important determinant of fibrinolytic rate. Transport by diffusion is slow and limited by the need for a high concentration gradient. Transport by convection is more efficient and depends on both the intrinsic resistance of the thrombus and on the effective pressure gradient. Animal experiments indicate that delivery of activator into a thrombus accelerates fibrinolysis and that fibrinolytic rate is dependent on the pressure gradient to which the clot is exposed. Clinical observations are consistent with a dominant role of transport in determining thrombolytic efficacy. Systemic thrombolysis is most successful in short clots exposed to a high pressure gradient, such as coronary artery thrombi in normotensive or hypertensive patients. Rapid lysis is also achieved by intrathrombic delivery of plasminogen activator into peripheral arterial clots and thrombosed dialysis access fistulas. In contrast, systemic thrombolysis is much less successful in clots that are exposed to an insufficient pressure gradient, such as venous thrombi and coronary thrombi of patients in cardiogenic shock.