Treatment for acute ischemic stroke has for years been frustrated by lack of efficacy. Despite a plethora of seemingly promising treatments from animal research, clinical application never came to fruition. Experience seems to indicate that the only truly effective treatment is the rapid restoration of perfusion to ischemic tissue prior to frank infarction. Unfortunately, every agent designed to achieve this goal met with the same ironic limitation; the ability to dissolve clot was coupled with the risk of causing intracerebral hemorrhage. Accordingly, stroke was addressed primarily through modification of risk factors and rehabilitation of the neurological sequelae. However, following the randomized trial of intravenous tissue-type plasminogen activator (t-PA) sponsored by the National Institutes of Neurological Disorders and Stroke (NINDS) in 1995, the first proven effective therapy for acute stroke became available. The door was finally open to emergency treatment of stroke in the acute phase. Moreover, the positive results of the NINDS trial appear to be independent of age. Nevertheless, intravenous thrombolysis remains ineffective in the majority of patients treated and is withheld from an even larger population because of presentation outside of the 3-hour therapeutic window. As a result, effective therapy is not available for most patients presenting with acute stroke. Recent advancements in the evaluation and treatment of acute ischemic stroke, including intra-arterial thrombolysis, mechanical thrombolysis, and combination therapies, hold significant promise for a larger proportion of patients. New imaging technology may also improve our ability to identify patients with viable brain tissue who may derive the greatest benefit from these therapies.