The treatment of acute stroke changed dramatically since the publication of the NINDS trail for IV rt-PA for acute stroke. While this was not the first trial, it was the first positive trial. Subsequently there has been an explosion in acute treatment modalities since the NINDS trial showed that acute stroke treatment is feasible. The following chapter reviews the thrombolysis trials, the inclusion and exclusion criteria of intravenous and intra-arterial use of pharmacologic and mechanical thrombolysis in acute ischemic stroke. Also discussed are the new pharmacotherapies and mechanical devices that will hopefully expand the treatment window and make thrombolysis safer and more effective.