Thrombolytic therapy has been shown to reduce thrombus burden in patients with acute pulmonary embolism (PE) faster than anticoagulation alone but is also associated with a significantly increased bleeding risk. Therefore, it is imperative that clinicians managing an acute PE have a thorough understanding of the pharmacology, indications, administration, and contraindications of thrombolytic therapy in this setting. Further, clinicians must be aware of appropriate treatment options should bleeding occur. In this handbook chapter, we provide a quick reference guide summarizing the literature and best practices when considering thrombolytic agents for acute PE.