Deep vein thrombosis (DVT) is a major health problem worldwide. The risk of pulmonary embolism following DVT is well established, but the long-term vascular sequelae of DVT are often underappreciated, costly to manage, and can have extremely detrimental effects on quality of life. Treatment of DVT classically involves oral anticoagulation, which reduces the risk of pulmonary embolism but does not remove the clot. Anticoagulation therefore does little to prevent the venous damage and scarring that occurs following DVT, leaving the patient at risk for permanent venous insufficiency and development of post-thrombotic syndrome (PTS). Catheter-directed thrombolysis (CDT) is a minimally invasive endovascular treatment that is used as an adjunct to anticoagulation. CDT lowers the risk of PTS by reducing clot burden and protecting against valvular damage. A catheter is advanced directly to the site of thrombosis under fluoroscopy followed by a slow, prolonged infusion of a relatively low dose of thrombolytic agent. CDT restores venous patency faster than anticoagulation, which hastens the relief of acute symptoms. Adjunctive CDT modalities have become increasingly popular among interventional radiologists, allowing for additional mechanical thrombectomy or ultrasound-enhanced thrombolysis at the time of catheter placement. These pharmacomechanical CDT (PCDT) techniques have the potential to reduce treatment time and associated healthcare costs. Numerous observational and retrospective studies have consistently shown a benefit of CDT plus anticoagulation over anticoagulation alone for prevention of PTS. Patients with long life expectancy and acute thrombosis involving the iliac and proximal femoral veins (iliofemoral DVT) have the greatest benefit from CDT, which may decrease the risk of PTS and/or decrease the severity of PTS symptoms if they do occur. Randomized controlled trials remain limited but generally support the observational data. CDT also plays an important role in those with acute limb-threatening venous occlusion or severe symptoms from DVT. Although adverse outcomes are rare, a potential devastating outcome is intracranial bleeding. While the available literature suggests the risk of serious morbidity from bleeding is quite rare, the absolute risk of bleeding is not clear and will require outcomes data from randomized trials. Future studies should also examine the cost-effectiveness of CDT for PTS prevention, particularly with respect to quality-adjusted life years, and compare the effectiveness of available PCDT devices.