Acute ischemic stroke is the leading cause of permanent disability and second leading cause of death worldwide. Over the past 10 years, mechanical thrombectomy has become a powerful technique for improving outcomes after large-vessel occlusion in patients with a small baseline infarct. Reperfusion in patients with extensive infarction has historically been considered futile or harmful. However, a recent series of trials showed that endovascular therapy benefits patients who present with extensive baseline infarction. These new data represent a paradigm shift in the approach to stroke therapy, leading to an expansion of indications. Therefore, more patients will benefit from mechanical thrombectomy. Furthermore, these data challenge current definitions of infarct and ischemia as seen on imaging. The data suggest a new era of reperfusion therapy that focuses on optimizing patient-specific approaches and developing adjunctive neuroprotectants and neurorestorative therapies.