S100 is a vertebrate-specific family of small, calcium-binding proteins. One of them is the S100B protein, mostly expressed in, and released by astroglial cells in the brain. The protein has been implicated in the regulation of numerous processes including phosphorylation of cytoskeletal proteins, cell proliferation and differentiation, as well as many other functions. This article focuses on the role of S100B in processes relating to learning and memory. More than four decades of behavioral and neurophysiological research have revealed beneficial effects of this protein. However, there is also evidence suggesting that overexpression of S100B can lead to memory dysfunction. It is possible that an increased S100B release from astrocytes may be co-responsible for memory dysfunction observed in the early stages of Alzheimer's disease.