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Patients with wake-up strokes account for approximately 1 in 5 individuals presenting with an acute ischemic stroke. However, they are commonly excluded from acute stroke treatment. This article reviews the current understanding of wake-up strokes. A comparison of wake-up and awake-onset strokes demonstrated that they are physiologically, clinically, and radiologically similar. Use of advanced CT and MRI techniques may help extend acute stroke treatment options to patients with wake-up stroke.