Wake-up strokes (WUS) are strokes with unknown exact time of onset as they are noted on awakening by the patients. They represent 20% of all ischemic strokes. The chronobiological pattern of ischemic stroke onset, with higher frequency in the first morning hours, is likely to be associated with circadian fluctuations in blood pressure, heart rate, hemostatic processes, and the occurrence of atrial fibrillation episodes. The modulation of stroke onset time also involves the sleep-wake cycle as there is an increased risk associated with rapid-eye-movement sleep. Furthermore, sleep may have an impact on the expression and perception of stroke symptoms by patients, but also on brain tissue ischemia processes via a neuroprotective effect. Obstructive sleep apnea syndrome is particularly prevalent in WUS patients. Until recently, WUS was considered as a contra-indication to reperfusion therapy because of the unknown onset time and the potential cerebral bleeding risk associated with thrombolytic treatment. A renewed interest in WUS has been observed over the past few years related to an improved radiological evaluation of WUS patients and the recent demonstration of the clinical efficacy of reperfusion in selected patients when the presence of salvageable brain tissue on advanced cerebral imaging is demonstrated.