The recently identified Mitochondrial Calcium Uniporter (MCU) is the protein of the inner mitochondrial membrane responsible for Ca2+ uptake into the matrix, which plays a role in the control of cellular signaling, aerobic metabolism and apoptosis. At least two properties of mitochondrial calcium signaling are well defined: (i) mitochondrial Ca2+ uptake varies greatly among different cells and tissues, and (ii) channel opening is strongly affected by extramitochondrial Ca2+ concentration, with low activity at resting and high capacity after cellular stimulation. It is now becoming clear that these features of the mitochondrial Ca2+ uptake machinery are not embedded in the MCU protein itself, but are rather due to the contribution of several MCU interactors. The list of the components of the MCU complex is indeed rapidly growing, thus revealing an unexpected complexity that highlights the pleiotropic role of mitochondrial calcium signaling. (C) 2014 Elsevier Inc. All rights reserved.