Thrombolytic agents are in widespread use for the dissolution of arterial and venous pathologic thrombi. Clinical settings where thrombolysis has played an important role include the acute coronary syndromes, peripheral arterial occlusion, ischemic stroke, deep venous thrombosis, and pulmonary embolism. Thrombolytic agents have been successfully employed in each of these areas, achieving dissolution of the occluding thrombus, reconstitution of blood flow, and improvement in the status of the tissue bed supplied or drained by the involved vascular segment. All clinically available thrombolytic agents act through cleavage of the plasminogen molecule to its active form, plasmin. Despite this similar mechanism of action, the thrombolytic agents differ in several biochemical parameters, including fibrin specificity, fibrin affinity, and relative resistance to inactivating factors in the plasma. Whether these differences account for significant differences in clinical outcome is a matter of some dispute. It is quite possible that in vitro biochemical differences do not have meaningful clinical correlates. However, there exists some evidence to suggest that differences in the risk of distant hemorrhage, idiosyncratic reactions, and the rapidity of clot dissolution do exist. An ideal agent for peripheral vascular thrombolysis would be one that was specific in its actions at the site of pathologic thrombi yet left the important and desirable pathologic thrombi that seal vascular defects unscathed. Although such an agent has not yet been identified, an understanding of the mechanism of action and principles underlying pharmacologic thrombolysis provides the necessary foundation of knowledge to choose a particular thrombolytic agent for a given clinical scenario.