Mitochondria match ATP supply to fluctuations in cellular energy requirements. Cellular energy requirements are often signaled to mitochondria by increases in the cytoplasmic concentration of Ca2+ ions. These increases in Ca2+ reach the mitochondrial matrix to regulate the proteins, enzymes and transporters required for mitochondrial ATP synthesis. Mitochondria may also limit energy demands by capturing the ion and shaping cytosolic Ca2+ signaling. Mitochondrial uptake of Ca2+ is driven by the substantial electrochemical gradient generated by the respiratory chain complexes. Although functional studies since the 1960s hinted at the nature of the Ca2+ channel involved, the molecular identity eluded physiologists until 2011 when the mitochondrial Ca2+ uniporter (MCU) gene was identified. MCU is a Ca2+-selective inwardly rectifying channel and a major pathway for the passage of Ca2+ ions from the cytoplasm into mitochondria. However, while well understood at the genetic and protein level, how MCU regulates cell function is unresolved. Understanding MCU regulation is of the utmost importance as disturbances in mitochondrial Ca2+ uptake accompanies several human diseases.