Ultrasound (US) has emerged as a new tool to treat ischemic stroke. The potential advantage of US is decreased risk of systemic bleeding complications due to its site-specific effect. Moreover, external application is noninvasive and is readily available. Experimental studies showed that low intensity (<or=2W/cm2) US safely enhanced thrombolytic drug activity within a wide range of frequencies (0.04-3.4 MHz). In humans, transcranial sonothrombolysis with mid-kHz frequencies showed an unacceptably high rate of intracranial bleeding, while the use of 2MHz yielded promising results in The Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic TPA (CLOTBUST) study. This study was a phase II randomized clinical trial that included patients with middle cerebral artery (MCA) occlusion within 3 h of stroke onset, who were treated with standard dose of tissue plasminogen activator (t-PA). Residual flow in MCA was monitored with 2MHz US in one group, and the rate of complete recanalization and dramatic clinical recovery significantly increased as compared to t-PA alone. This chapter further discusses diagnosis of an acute occlusion and recanalization using the thrombolysis in brain ischemia (TIBI) waveform flow grading scale, application of fast track insonation protocol, and administration of US. Also, the potential enhancement of sonothrombolysis with microbubbles is discussed.