Calcium lons as second messengers control many biological processes, at least in part, via interaction with a large number of Ca(2+)-binding proteins. One class of these proteins shares a common Ca(2+)-binding motif, the EF-hand, Here, we describe some functional aspects of EF-hand proteins, which have been found recently in different cellular compartments. Novel links between EF-hand proteins, particularly S100 proteins, and specific diseases are now emerging.