The structurally related, low-molecular weight S100 proteins constitute a family of proteins that possess a common basic structure allowing them to carry out a range of intracellular and extracellular functions. Unifying intracellular functions relate to regulation of proliferation, energy metabolism, calcium homeostasis, enzyme activities, cell growth and differentiation. Extracellular tasks, however, appear somewhat specific to select S100 members and include participation in innate and adaptive immune responses, tissue development and repair, and/or cell migration and chemotaxis. This review is an attempt to comprehensively summarize the function and expression of S100 proteins selectively expressed in normal skin and/or involved in diseased skin.