Systemic administration of tissue plasminogen activator (tPA) remains the fastest way to initiate treatment for acute ischemic stroke. The presence of a proximal arterial occlusion should not be viewed as an insurmountable predictor of tPA failure. Because tPA works by induction of partial recanalization of large thrombi, early augmentation of fibrinolysis to improve recanalization is desirable. This augmentation is feasible and can be safely achieved at the bedside with diagnostic Doppler ultrasound. In the CLOTBUST trial, 83% of patients achieved any recanalization (46% complete, 27% partial) with tPA+transcranial Doppler vs 50% (17% complete, 33% partial) with tPA alone within 2 hours of treatment ( P <0.001). Sustained, complete recanalization at 2 hours was 38% vs 13%, respectively ( P =0.03). A recent meta-analysis of 6 randomized and 3 nonrandomized clinical studies of sonothrombolysis showed that any diagnostic ultrasound monitoring can at least double the chance of early complete arterial recanalization at no increase in the risk of symptomatic intracerebral hemorrhage. Because application in humans of frequencies below the diagnostic range resulted in increased symptomatic bleeding rates, mechanisms by which megahertz and kilohertz frequencies interact with the clot–residual flow interface and endothelium are currently under renewed investigations. Catheter-based ultrasound delivery to arterial thrombi and intraventricular clots is the subject of ongoing clinical trials. Addition of gaseous perflutren-lipid microspheres to tPA and transcranial Doppler can further facilitate early flow improvement, with a 50% rate of early, complete recanalization in a recent feasibility study. Transcranial ultrasound delivery in an operator-independent and dose-controlled manner is being tested in a clinical trial.