S100 belongs to the family of calcium binding proteins. S100A and S100B proteins are two members of the S100 family. S100A is composed of an alpha and beta chain whereas S100B is composed of two beta chains. S-100 protein has been found in normal melanocytes, Langerhans cells, histiocytes, chondrocytes, lipocytes, skeletal and cardiac muscle, Schwann cells, epithelial and myoepithelial cells of the breast, salivary and sweat glands, as well as in glial cells. Neoplasms derived from these cells also express S-100 protein, albeit non-uniformly. A large number of well-differentiated tumors of the salivary gland, adipose and cartilaginous tissue, and Schwann cell-derived tumors express S-100 protein. Almost all malignant melanomas and cases of histiocytosis X are positive for S-100 protein. Despite the fact that S-100 protein is an ubiquitous substance, its demonstration is of great value in the identification of several neoplasms, particularly melanomas and their metastases.