Antibodies reactive with S100 protein are useful markers in a diagnostic immunohistochemistry laboratory dealing with cutaneous tumors. However, S100 protein is not a single protein but instead a group of S100 proteins with diverse functions. S100 proteins constitute a family of acidic calcium-binding proteins that are important in intracellular calcium metabolism. Recent evidence that some S100 proteins are secreted makes it likely that they are also involved in cell-cell interactions. The exploration of the status of the different members of the S100 family may yield not only diagnostic clues but also relevant functional information about the cells. Considerable recent progress has been made in our understanding of S100 proteins. This review surveys some of these findings that may be either directly or indirectly relevant to cutaneous pathology.