The US Food and Drug Administration (FDA) approved the use of intravenous (IV) recombinant tissue plasminogen activator (rt-PA) in 1996, on the basis of the results of the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study. IV rt-PA therapy at a dose of 0.9 mg/kg has been approved internationally for the treatment of hyperacute ischemic stroke. After a dose comparison study using duteplase and a multicenter study using a single dose of alteplase (Japan Alteplase Clinical Trial: J-ACT), the administration of IV rt-PA therapy at a dose of 0.6 mg/kg was approved in Japan in 2005. Immediately after the approval, the Japan Stroke Society published the Japanese guidelines for this low-dose therapy. Two years after the approval in Japan, the outcome of IV rt-PA therapy in Japan was observed to be comparable to that of NINDS rt-PA therapy and to those published in studies based in Western nations. Several trials have reported predictors of unfavorable outcome for IV rt-PA therapy. Patients with severe strokes (higher NIHSS score, coma), higher age at disease onset, aortic arch dissection, higher blood pressure, higher blood sugar, occlusion of the internal carotid artery (ICA) or tandem lesion of the left ICA and right middle cerebral artery (MCA), or the presence of major early ischemic changes as observed upon computed tomography (CT) or magnetic resonance imaging (MRI), showed a greater probability for unfavorable response to treatment. The results of the randomised 2008 trial conducted by the third European Cooperative Acute Stroke Study (ECASS III) suggested that treatment with IV rt-PA administered 3-4.5 hours after symptom onset can still induce significant improvement in clinical outcomes after an acute ischemic stroke as opposed to a placebo. MRI-based thrombolysis might be safer than standard CT-based thrombolysis. A combination of reperfusion therapies, IV rt-PA and sonothrombolysis, neuroprotective agents or antiplatelet agents may be effective. However, currently available data do not provide conclusive evidence for the safety or efficacy of these combination therapies. Patients having ICA occlusion may require alternatives including a higher dose of alteplase, combined IV/IA thrombolysis, or possibly mechanical thrombectomy by using a thrombus-removal device.