The use of catheter-directed thrombolysis is a proven treatment for arterial ischemia, deep vein thrombosis, and severe pulmonary embolism. For arterial ischemia, thrombolysis has resulted in improved amputation-free survival and fewer subsequent surgeries to reestablish blood flow to the ischemic limb. The management of patients with thromboembolic diseases is complex, and the multiple thrombolytic drugs available to choose from compound this complexity. Although some believe the available thrombolytic agents are interchangeable, real biochemical differences exist that may prove otherwise. This article describes these pharmacologic differences and how they may affect the clinical practice of catheter-directed thrombolysis.