The processes of excitation-contraction (EC) coupling consume large amounts of energy that need to be replenished by oxidative phosphorylation in the mitochondria. Since Ca(2+) activates key enzymes of the Krebs cycle in the mitochondrial matrix, it is important to understand the mechanisms and kinetics of mitochondrial Ca(2+) uptake to delineate how in cardiac myocytes, energy supply is efficiently matched to demand. In recent years, the identification of various proteins involved in mitochondrial Ca(2+) signalling and the tethering of mitochondria to the sarcoplasmic reticulum (SR) has considerably advanced the field and supported the concept of a mitochondrial Ca(2+) microdomain, in which Ca(2+) concentrations are high enough to overcome the low Ca(2+) affinity of the principal mitochondrial Ca(2+) uptake mechanism, the Ca(2+) uniporter. Furthermore, defects in EC coupling that occur in heart failure disrupt SR-mitochondrial Ca(2+) crosstalk and may cause energetic deficit and oxidative stress, both factors that are thought to be causally involved in the initiation and progression of the disease.