In recent years there has been a proliferation of interest in the brain-specific protein S100B, its many physiologic roles, and its behaviour in various neuropathologic conditions. Since the mid-1960s, its wide variety of intracellular and extracellular activities has been elucidated, and it has also been implicated in an increasing number of central nervous system (CNS) disorders. S100B is part of a superfamily of proteins, some of which (including S100B) have been implicated as calcium-dependent regulatory proteins that modulate the activity of effector proteins or cells. S100B is primarily an astrocytic protein. Within cells, it may have a role in signal transduction, and it is involved in calcium homeostasis. Information about the functional implication of S100B secretion by astrocytes into the extracellular space is scant but there is substantial evidence that secreted glial S100B exerts trophic or toxic effects depending on its concentration. This review summarises the historic development and current knowledge of S100B, including recent interesting findings relating S100B to a diversity of CNS pathologies such as traumatic brain injury, Alzheimer's disease, Down's syndrome, schizophrenia, and Tourette's syndrome. These broad implications have led some workers to describe S100B as ‘the CRP (C-reactive protein) of the brain.’ This review also examines S100B's potential role as a neurologic screening tool, or biomarker of CNS injury, analogous to the role of CRP as a marker of systemic inflammation. © 2007 Wiley-Liss, Inc.