Intravenous administration of recombinant tissue plasminogen activator (rt-PA) remains the effective way to treat for acute ischemic stroke. Recently, sonothrombolysis by using both rt-PA and transcranial Doppler (TCD) which are able to observe the microembolic signals and the recanalization of cerebral arterial occlusion is a new and an additional treatment approach. Experimental studies have shown that thrombolysis with rt-PA can be enhanced with ultrasound. Ultrasound delivers mechanical pressure waves to the clot, thus exposing more thrombus surface to circulating drug. Based on these findings, the CLOTBUST trial revealed that 83% of patients achieved any recanalization (46% complete, 27% partial) with rt-PA+TCD vs 50% (17% complete, 33% partial) with rt-PA alone within 2 hours of treatment (P<0.001). Several clinical studies of sonothrombolysis showed that any diagnostic ultrasound monitoring can at least double the chance of complete arterial recanalization at no increase in the incidence of symptomatic intracerebral hemorrhage. Addition of gaseous perflutren-lipid microspheres to rt-PA and ultrasound monitoring can further facilitate early flow improvement, with a 50% rate of early, complete recanalization in a recent study. Catheter-based ultrasound delivery to arterial thrombi is the subject of ongoing clinical trials. Long-term outcome remains a major concern in the further development of sonothrombolysis.