Intravenous tissue plasminogen activator (tPA) remains the only approved, fastest and widely feasible treatment of acute ischemic stroke. Systemic tPA induces recanalization of an occluded vessel, the process thought to lead to neurological recovery. Augmentation of this fibrinolytic activity can be safely achieved with diagnostic ultrasound frequencies and intensities. Ultrasound delivers mechanical pressure waves to thrombi exposing more thrombus surface to circulating drug. International multi-center CLOTBUST trial showed that patients with acute stroke treated with sonothrombolysis (tPA+2 MHz TCD) had more dramatic clinical recovery coupled with arterial recanalization (25% vs 8%) at no increase in the risk of symptomatic intracerebral hemorrhage (sICH). Based on this trial and subsequent phase I–II studies of a novel operator-independent device for delivery of the CLOBUST levels of ultrasound energy, a phase III efficacy trial of sonothrombolysis (named CLOTBUSTER) is being launched in Europe and North America.