About 25% of all strokes occur during sleep, i.e., without knowledge of exact time of symptom onset. According to licensing criteria, this large group of patients is excluded from treatment with received tissue-plasminogen activator, the only specific stroke treatment proven effective in large randomized trials. This paper reviews clinical and imaging characteristics of wake-up stroke and gives an update on treatment options for these patients. From clinical and imaging studies, there is evidence suggesting that many wake-up strokes occur close to awakening and thus, patients might be within the approved time-window of thrombolysis when presenting to the emergency department. Several imaging approaches are suggested to identify wake-up stroke patients likely to benefit from thrombolysis, including non-contrast CT, CT-perfusion, penumbral MRI, and the recent concept of diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR). A number of small case series and observational studies report results of thrombolysis in wake-up stroke, and no safety concerns have occurred, while conclusions on efficacy cannot be drawn from these studies. To this end, there are ongoing clinical trials enrolling wake-up stroke patients based on imaging findings, i.e., the DWI-FLAIR-mismatch (WAKE-UP) or penumbral imaging (EXTEND). The results of these trials will provide evidence to guide thrombolysis in wake-up stroke and thus, expand treatment options for this large group of stroke patients.