We provide a critical analysis of the relevance of S100B in acute brain injury emphazising the beneficial effect of its biological properties. S100B is a calcium-binding protein, primarily produced by glial cells, and exerts auto- and paracrine functions. Numerous reports indicate, that S100B is released after brain insults and serum levels are positively correlated with the degree of injury and negatively correlated with outcome. However, new data suggest that the currently held view, that serum measurement of S100B is a valid "biomarker" of brain damage in traumatic brain injury (TBI), does not acknowlege the multifaceted release pattern and effect of the blood-brain barrier disruption upon S100B levels in serum. In fact, serum and brain S100B levels are poorly correlated, with serum levels dependent primarily on the integrity of the blood-brain barrier, and not the level of S100B in the brain. The time profile of S100B release following experimental TBI, both in vitro and in vivo, suggests a role of S100B in delayed reparative processes. Further, recent findings provide evidence, that S100B may decrease neuronal injury and/or contribute to repair following TBI. Hence, S100B, far from being a negative determinant of outcome, as suggested previously in the human TBI and ischemia literature, is of potential therapeutic value that could improve outcome in patients who sustain various forms of acute brain damage.