In patients with extensive lower limb deep vein thrombosis (DVT) that, typically, extends into the iliofemoral veins, catheter-directed thrombolysis (CDT) can achieve faster and more complete thrombus lysis as compared with systemic thrombolysis, while providing an acceptable safety profile through administration of lower doses of thrombolytic agents. Through a reduction in thrombus burden, CDT has the potential to mitigate the risk for post-thrombotic syndrome by restoring venous patency and preserving venous valve function. The efficacy of CDT may be improved by adjunctive approaches that include percutaneous mechanical thrombectomy, angioplasty with or without stenting, and ultrasound-assisted CDT. CDT may also have a specific therapeutic role in the management of iliofemoral DVT involving patients who are pregnant or with May-Thurner syndrome. This article summarizes the literature in this area and discusses recently completed and ongoing randomized trials on the use of CDT in patients with extensive lower limb DVT.