After the success of the 1995 National Institutes of Neurological Disorders and Stroke (NINDS) study using intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA, alteplase) within 3 hours in acute stroke, this therapy was approved worldwide and has been a standard therapy for acute stroke patients. In Japan, IV alteplase at a dose of 0.6 mg/kg was approved in 2005 after a multicenter study using this low dose of alteplase (Japan Alteplase Clinical Trial [J-ACT]). IV rt-PA can drastically improve stroke outcomes. However, more than half of treated patients are not independent in the chronic stage. In addition, the therapeutic time window was so limited that many stroke patients do not have a chance to receive the therapy. In 2008, European Cooperative Acute Stroke Study III showed that IV rt-PA administered between 3 and 4.5 hours after stroke onset significantly improved clinical outcomes in stroke patients; the success resulted in the renewal of recommendation in guidelines in Europe, Canada, and the United States. Several therapeutic strategies, including endovascular therapy, sonothrombolysis, and neuroprotective therapy, may improve the efficacy of IV rt-PA.