Achieving rapid reperfusion transcranial color-coded duplex is the critical issue in acute stroke treatment. Ultrasound (US) generates negative pressure waves that are associated with an increase in either intrinsic or intravenous tissue plasminogen activator (tPA)-induced fibrinolytic activity. Higher rates of tPA-induced arterial recanalization, associated with a trend towards better functional outcome, have been safely achieved by using high-frequency US. By contrast, the use of low-frequency US and transcranial color-coded duplex has been linked to significant hemorrhagic complications. US-accelerated thrombolysis has been safely enhanced by lowering the amount of energy needed for acoustic cavitation with the administration of microbubbles. Other applications of US are being studied, including its intra-arterial use. Operator-independent devices, which will spread the use of these US techniques further, are also being developed. This article reviews the present status of sonothrombolysis in acute stroke treatment, highlighting both experimental and clinical studies addressing this issue, and discusses its future regarding both efficacy and safety.