Iliofemoral deep vein thrombosis (DVT) is associated with serious short- and long-term physical, social, and economic sequelae for patients. Most physicians treat patients with acute iliofemoral DVT in the same manner as they treat all acute DVT patients: with anticoagulation alone. Yet a growing body of evidence suggests that, in this subset of DVT patients, a treatment strategy that includes thrombus removal plus optimal anticoagulation significantly improves outcomes. This article reviews the evidence supporting this strategy and discusses current and promising techniques of thrombus removal, including contemporary venous thrombectomy, intrathrombus catheter-directed thrombolysis, and pharmacomechanical thrombolysis.