Intravenous administration of recombinant tissue-plasminogen activator (rt-PA) remains the fastest and widely feasible strategy to initiate treatment in acute ischemic stroke. Because it works by inducing recanalization of an occluded vessel, augmentation of this process is desirable and diagnostic transcranial Doppler (TCD) ultrasound can accomplish this safely. A 2-MHz pulsed-wave monitoring can at least double the chance of early complete arterial recanalization at no increase in the risk of symptomatic intracerebral hemorrhage. Gaseous microspheres, initially developed as ultrasound contrast agents, can further increase the effectiveness of rt-PA. A recent microsphere dose-escalation study called TUCSON showed sustained complete recanalization rates of 67% in patients receiving TCD monitoring with a 1.4-mL perflutren-lipid microsphere dose compared with controls receiving rt-PA alone with no increase in hemorrhage rate. In this article, we review the current and emerging applications of ultrasound and microspheres in stroke management including augmentation of systemic thrombolysis and implications for future reperfusion strategies.