S100 is a multigenic family of non-ubiquitous Ca(2+)-modulated proteins of the EF-hand type expressed in vertebrates exclusively and implicated in intracellular and extracellular regulatory activities. Within cells, most of S100 members exist in the form of antiparallelly packed homodimers (in some cases heterodimers), capable of functionally crossbridging two homologous or heterologous target proteins in a Ca(2+)-dependent (and, in some instances, Ca(2+)-independent) manner. S100 oligomers can also form, under the non-reducing conditions found in the extracellular space and/or within cells upon changes in the cell redox status. Within cells, S100 proteins have been implicated in the regulation of protein phosphorylation, some enzyme activities, the dynamics of cytoskeleton components, transcription factors, Ca(2+) homeostasis, and cell proliferation and differentiation. Certain S100 members are released into the extracellular space by an unknown mechanism. Extracellular S100 proteins stimulate neuronal survival and/or differentiation and astrocyte proliferation, cause neuronal death via apoptosis, and stimulate (in some cases) or inhibit (in other cases) the activity of inflammatory cells. A cell surface receptor, RAGE, has been identified on inflammatory cells and neurons for S100A12 and S100B, which transduces S100A12 and S100B effects. It is not known whether RAGE is a universal S100 receptor, S100 members interact with other cell surface receptors, or S100 protein interaction with other extracellular factors specifies the biological effects of a given S100 protein on a target cell. The variety of intracellular target proteins of S100 proteins and, in some cases, of a single S100 protein, and the cell specificity of expression of certain S100 members suggest that these proteins might have a role in the fine regulation of effector proteins and/or specific steps of signaling pathways/cellular functions. Future analyses should discriminate between functionally relevant S100 interactions with target proteins and in vitro observations devoid of physiological importance.