The goal of a therapeutic intervention should be to positively impact a meaningful patient outcome. Too often, though, efficacy of a treatment is based on a surrogate endpoint. Thrombolytic therapy for venous thromboembolic disease is an example of a treatment whose success is primarily based on radiographic or echocardiographic endpoints and not endpoints such as symptom relief, functional capacity, quality of life, thrombosis recurrence, and survival. Thrombolysis for lower-extremity deep venous thrombosis does not reduce the incidence of pulmonary embolism, has unclear impact on the rates of post-thrombotic syndrome, and is associated with increased rates of major hemorrhage compared to conventional anticoagulation. Reserving thrombolysis for limb-threatening thrombosis especially in the young seems prudent. Currently available evidence does not support the routine use of thrombolytic therapy in patients with hemodynamically stable pulmonary embolism regardless of right ventricular function status. Risks, benefits, and alternative therapies must always be considered, and therapy must be guided by individual case circumstances and the best available scientific evidence.