The members of the S100 protein family are multifunctional proteins with a regulatory role in a variety of cellular processes. They exert their actions usually through calcium binding, although Zn2+ and Cu2+ have also been shown to regulate their biological activity. The most studied member, protein S100B, exhibits neurotrophic (at physiologic concentration) or neurotoxic (at higher concentration) activity and its immunohistochemical expression or serum levels have been determined in various clinical disorders. S100B has been well documented as a marker of astrocytic activation mediating its effects via interaction with receptor for advanced glycation end products (RAGE). We herein provide a wide range of information concerning their clinical application in traumatic brain injuries, Alzheimer disease, subarachnoid haemorrhage and other neurologic disorders, malignant melanoma and several other neoplasms (as S100B has been shown to down-regulate p53), as well as inflammatory diseases. Also its use on predicting neurologic outcome after resuscitation for cardiac arrest or in intrauterine growth retardation newborns is discussed.