In the course of evolution, Ca2+ has emerged as the most versatile intracellular messenger. Its concentration within cells is controlled by reversible binding to specific classes of proteins that act as Ca2+ sensors to decode its information before passing it on to targets. The decoding operation is based on specific conformational changes in the sensor proteins. Other proteins intrinsic to membranes simply control Ca2+ concentration without processing its message, by transporting it across membrane boundaries. They are located in the plasma membrane and in the membranes of the organelles (the endo(sarco)plasmic reticulum, the mitochondria, the nuclear envelope), which play distinctive roles in the cellular homeostasis of Ca2+. Ca2+ is an ambivalent signaling agent. It carries information to virtually all processes important to cell life (e.g., it couples excitation to contraction, secretion, gene transcription, and controls enzyme activity through protein phosphorylation-dephosphorylation), but also transmits signals that promote the programmed demise of cells. When escaping control, Ca2+ also precipitates toxic cell death.