Stroke is a common cause of death and disability throughout the world. Acute neurologic deficits due to ischemic injury deserve rapid recognition and diagnosis in order to provide effective therapy. Intravenous tissue plasminogen activator (t-PA) provided to carefully selected patients that can be treated within 3 hours of stroke onset results in improved outcome in these patients. Intra-arterial administration of t-PA within a 6-hour window is performed at several academic centers in patients with middle cerebral and other intracranial artery occlusions based on results of one randomized clinical trial and numerous case reports. Although acute therapy of ischemic stroke has received much attention since the approval of intravenous t-PA, only a small percentage of individuals suffering a stroke actually receive t-PA. This article will review the optimal management of the acute stroke patient and discuss thrombolytic clinical trials that have been completed as well as those that are in progress.