Advances in the understanding of a class of Ca(2+)-binding proteins usually referred to as "Ca(2+) buffers" are reported. Proteins historically embraced within this group include parvalbumins (alpha and beta), calbindin-D9k, calbindin-D28k and calretinin. Within the last few years a wealth of data has accumulated that allow a better understanding of the functions of particular family members of the >240 identified EF-hand Ca(2+)-binding proteins encoded by the human genome. Studies often involving transgenic animal models have revealed that they exert their specific functions within an intricate network consisting of many proteins and cellular mechanisms involved in Ca(2+) signaling and Ca(2+) homeostasis, and are thus an essential part of the Ca(2+) homeostasome. Recent results indicate that calbindin-D28k, possibly also calretinin and oncomodulin, the mammalian beta parvalbumin, might have additional Ca(2+) sensor functions, leaving parvalbumin and calbindin-D9k as the only "pure" Ca(2+) buffers.