Treatment with intravenous tissue plasminogen activator (IV tPA) alone is associated with an estimated 40% efficacy in early recanalization of major coronary artery (MCA) occlusions. AIS still has almost a 60% rate of mortality or disability in patients treated with IV tPA, despite aggressive therapy. Endovascular treatment is currently being researched. The IA administration of tPA is safe and effective, but remains an unapproved, off-label treatment for AIS. Hypothesized advantages of intra-arterial tPA include direct visualization of acute large vessel thrombi; the ability to customize the tPA dose and location of drug delivery based on features of the individual clot, and potentially more complete thrombolysis. This paper exams the evidence on Intraarterial tPA administration versus IV tPA in patients outside of the 4.5 hr treatment window established by the FDA.