In 1883, Ringer showed that to get isolated hearts to contract, it was necessary to have Ca2+ ions in the perfusion medium [421]. This was the first demonstration of the critical role of calcium in cellular activity. Remarkably, a hundred years passed before the importance of calcium was recognized in processes other than muscle contraction, and almost as long before the cellular mechanisms responsible for calcium regulation started to be understood. Nowadays, it is acknowledged that calcium is the most ubiquitous intracellular signaling molecule and that the concentration of Ca2+ ions is under very tight and dynamic control in all major cell compartments (cytoplasm, nucleus, endoplasmic reticulum, mitochondria). In each compartment, this control is achieved through the interplay of transmembrane entry and extrusion systems (channels, exchangers, and transporters) and of buffering systems (Ca2+-binding proteins). Some of these buffers also participate in the further processing of the Ca2+ concentration signals. An excellent general review by Brini and Carafoli [61] provides detailed information on intracellular calcium signaling and more specific papers are available on Ca2+ stores in the endoplasmic reticulum [463], in the nucleus [50], and in mitochondria [137, 422].