Abstract The publication of the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial in 1995 generated considerable hope, but also concerns as to whether the results of this carefully conducted randomized clinical trial can be replicated in routine clinical practice. Steadily accumulating data on use of intravenous t-PA for acute ischemic stroke from multiple postmarketing studies encouragingly show that low complication rates and high rates of favorable outcome can be achieved with proper use of this therapy; however, preliminary data also show that the general applicability of t-PA is uncertain, and the risk of t-PA might potentially outweight the benefits in some circumstances. Ongoing systemic audits of t-PA use in routine clinical practice have proved useful and provide insight regarding the effect of thrombolysis in different clinical settings. Treatment with t-PA should be used by physicians who are well educated and experienced with its use, patients should be carefully selected, and treatment guidelines must be strictly adhered to. The option of treatment with t-PA is available to a small fraction of patients afflicted with acute stroke, but the proportion of patients who can be treated effectively with thrombolysis has been shown to grow with experience and better organization. Door-to-needle time in most series exceeds the recommended 60-minute goal. Over the last 5 years, large strides were made toward effective urgent therapy with t-PA, but much further work is still required to maximize the benefit for stroke victims. Modern neurovascular imaging techniques might allow for treatment to be appropriately tailored to the individual patient. For now, the original NINDS protocol for patient selection and treatment has borne itself out and remains the standard of care for acute ischemic stroke.