In the pivotal clinical trials of intravenous tissue plasminogen activator (TPA) therapy for ischemic stroke, a low rate of early arterial recanalization was suspected due to the small numbers of patients who had early dramatic clinical improvement. TPA activity can be enhanced with ultrasound including 2 MHz transcranial Doppler (TCD). TCD can identify residual signals around the thrombus with the thrombolysis in brain ischemia (TIBI) flow grading system and therefore expose more thrombus surface to circulating TPA. A phase I clinical study, monitoring TPA infusion with diagnostic ultrasound resulted in an unexpectedly high rate of complete recanalization (36% of proximal middle cerebral artery (MCA) occlusions) and associated early dramatic clinical recovery (24%) among treated patients. The external application of diagnostic ultrasound in our studies raised the possibility that a synergistic TPA and ultrasound action accelerated flow improvement and achieved faster and more complete thrombus dissolution as predicted from experimental models. The CLOTBUST (combined lysis of thrombus in brain ischemia using transcranial ultrasound and systemic TPA) trial is testing this hypothesis in a phase II clinical randomized multi-center setting. Dramatic clinical recovery from stroke and complete recanalization shortly after TPA bolus are feasible goals for thrombolysis assisted with TCD monitoring.