Systemic treatment with rtPA approved for a 3-hour window is the only established causal therapy for acute stroke in the United States and Canada. Thrombolytic therapy with rtPA demonstrated a small, although significantly reduced morbidity, in a limited number of highly selected patients. As recently shown, intraarterial application is favorable and opens the window of treatment up to 6 hours. The combination of ultrasound with thrombolytic agents may further enhance the potential benefit by means of enzymatic-mediated thrombolysis, which has been demonstrated in different in vitro and in vivo experiments for an accelerated recanalization of occluded peripheral and coronary vessels. Whereas no or only small attenuation of ultrasound can be expected through skin and chest, intensity will be significantly attenuated if penetration of the skull is required. The transcranial penetration of ultrasound increases when the frequency is decreased to 20 kHz and may be transmitted through the skull transtemporally with tolerable attenuation up to 200 kHz. This results in efficacy in vitro with low intensities of 0.5-2.0 W/cm(2) systemic treatment with rtPA approved for a 3-hour window in the nonfocused ultrasound field. Application of ultrasound insonation increased rtPA-mediated thrombolysis up to 20% in a static model; meanwhile, it enhanced the recanalization rate from 30%-90% in a flow model. In vitro results suggest that 1 MHz ultrasound with 0.5 W/cm(2), established for diagnostic purposes, may already enhance rtPA- mediated thrombolysis. Before therapeutic ultrasound can be tested clinically in acute stroke, safety of transcranial exposure of the brain has to be confirmed. To date, animal experiments suggested no harm to the blood brain barrier or systemic heating with 2 W/cm(2). This combined treatment is one perspective in optimizing therapy in acute stroke within the acute phase and may be applied easily with few limitations.