This policy was developed by a joint writing panel of the American College of Emergency Physicians and the American Academy of Neurology. The panel reviewed the literature to derive evidence-based recommendations to help clinicians answer the following critical questions: (1) Is intravenous tissue plasminogen activator (tPA) safe and effective for acute ischemic stroke patients if given within 3 hours of symptom onset? (2) Is intravenous tPA safe and effective for acute ischemic stroke patients treated between 3 to 4.5 hours after symptom onset? Evidence was graded and recommendations were given based on the strength of the available data in the medical literature.