This chapter recounts the history of thrombolytic agents, those agents currently available, and indications for use. Clinical agents have expanded over the 80 years since they were discovered, primarily in the pleural space. Thrombolytic agents can be administered systemically (i.e., intravenously) to treat ischemic stroke, massive pulmonary embolism (PE), and acute myocardial infarction. They also can be delivered directly to the site of a thrombus via catheter, also known as catheter-directed therapy (CDT). To perform CDT safely and effectively, an understanding of the pharmacology and technical aspects of delivering agents is critical. This chapter will review in detail the indications for use, contraindications to CDT, technical aspects, and specific recommendations for monitoring during use.