The National Institute of Neurological Disorders and Stroke trial of recombinant tissue plasminogen activator has been considered a landmark study in the acute treatment of ischemic stroke. Unfortunately, only a small percentage of all ischemic stroke patients presents to the hospital in time to receive the drug. Moreover, the recannalization rate of a major artery occlusion, such as the proximal middle cerebral artery or top of the internal carotid artery occlusion, after intravenous (IV) thrombolytic therapy has been disappointingly low. Since the Food and Drug Administration's approval of IV plasminogen activator, there have been numerous randomized clinical trials investigating the safety and efficacy of different thrombolytics administered in various time frames. In addition to the IV administration, efforts have been made in order to study the radiographic as well as clinical effects of intra-arterial (IA) thrombolysis. The combination of IV and IA thrombolysis has been studied. For patients who do not qualify for receiving chemical thrombolysis, new devices have been developed for mechanical thrombectomy.