Tremendous advancements in the treatment of acute ischemic stroke in the last 25 years have been based on the principle of reperfusion in early time windows and identification of small core infarct for intravenous thrombolysis and mechanical thrombectomy. Advances in neuroimaging have made possible the safe treatment of patients with acute ischemic stroke in longer time windows and with more specific selection of patients with salvageable brain tissue. In this review, we discuss the history of endovascular stroke thrombectomy trials and highlight the neuroimaging-based trials that validated mechanical thrombectomy techniques in the extended time window with assessment of penumbral tissue. We conclude with a survey of currently open trials that seek to safely expand eligibility for this highly efficacious treatment.