The time span from symptom onset to treatment initiation remains a critical variable determining the efficacy of thrombolysis in acute ischemic stroke. To date, performing a brain scan is indispensable prior to therapy in order to differentiate between patients with ischemic stroke and those with intracerebral hemorrhage (ICH). This causes substantial treatment delay, as thrombolysis cannot be applied prior to hospital admission at much earlier time points. Recently, brain-specific astroglial proteins (i.e., glial fibrillary acidic protein (GFAP), S100B) were identified to be released rapidly from the cytoplasm of destroyed cells in case of acute ICH. Elevated serum concentrations were found within the first 6 h after ICH onset. In contrast, in ischemic stroke, these proteins are released with delay, mirroring the more gradual occurrence of necrotic cell death and blood brain barrier disruption. S100B and GFAP may qualify as candidate serum biomarkers which are able to differentiate between ischemic stroke and ICH in the emergency phase of stroke. This minireview enlightens the pathophysiological background of this finding and provides an overview on currently available clinical data.