Glia play active and vital roles in the CNS, including regulation of brain development, maintenance of cellular homeostasis and reparative responses to acute and chronic neurologic insults. However, in pathological conditions, glial function may be dysregulated resulting in enhanced neuroinflammation and further neurologic injury. The fundamental concept that aberrant regulation of a normally beneficial process may instead result in pathology is exemplified by the properties of the glial-derived protein, S100B. In the developing brain and following acute glial activation in response to injury, S100B acts as a neurotrophic factor and neuronal survival protein. In contrast, overproduction of S100B by activated glia can lead to exacerbation of neuroinflammation and neuronal dysfunction. This duality of S100B actions, both reparative and degenerative, is consistent with the compelling clinical evidence of the association between increases in S100B levels and outcome following brain injury. S100B levels generally correlate with the severity of damage and may have predictive value for adverse neurological outcomes. The cumulative data support the potential of S100B as a biomarker for brain damage, implicate glial activation as a possible treatment target in acute and chronic CNS disorders, and highlight the dual role of glia in the reparative and pathologic responses to neurologic injury.