This article reviews some of the current literature in support or against extension of the intravenous tissue plasminogen activator window, use of intra-arterial therapy or devices, as well alternative pharmacologic therapies that may extend the window for treatment of patients with acute ischemic stroke, with consideration of the relative risk of thrombolytic complications, factors for worse outcomes, and unclear stroke onset, as seen in patients with wake-up stroke. The issue of newer concomitant antithrombotic therapies as they affect the decision for acute ischemic stroke thrombolytic therapy is also explored.