Ischemic stroke is most often caused by an acute extracranial or intracranial thromboembolic lesion obstructing an artery. It has been demonstrated that recanalization is the most important modifiable predictor of a good clinical outcome. Reperfusion strategies focus on early reopening of the vessel to reestablish antegrade flow within the penumbra.Current standard therapy within 4.5 h is intravenous thrombolysis (IVT) with tissue plasminogen activator (tPA, 0.9 mg/kg body weight, maximum dose 90 mg). Thrombolytic therapy appears to be safe and effective across various types of hospitals, if the treatment is conducted by a physician with stroke expertise.New imaging methods (MR diffusion/perfusion, CT perfusion) are being investigated in order to better select patients who are most likely to benefit from recanalization therapy based on current clinical evidence. Neither perfusion imaging with CT or MR nor the mismatch concept are recommended for routine treatment decisions within or beyond the 4.5 h available for IVT.If major vessel occlusion is proven but IVT is contraindicated, intra-arterial thrombolysis (IAT) with tPA or mechanical thrombectomy with the Merci Retriever or Penumbra System may be a treatment option. The availability of IAT generally should not preclude the intravenous administration of tPA in otherwise eligible patients. Intra-arterial treatment can be performed within 8 h after stroke onset. Combining intravenous tPA pretreatment with subsequent IAT or mechanical thrombectomy may improve the recanalization rate and may be used as a rescue therapy in cases of persistent major vessel occlusion after unsuccessful IVT.Despite testing, no thrombolytic agent other than tPA (e.g., IIb/IIIa antagonists, heparin, etc.) has yet been approved for routine practice for either intravenous or intra-arterial application, alone or in combination with tPA.Continuous transcranial Doppler (TCD) monitoring of an occluded vessel may increase the rate of early recanalization after tPA; this effect may be facilitated by the administration of microbubbles. This method is still considered experimental.