Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P_i, and Ca²⁺. However, the kinetics of mitochondrial Ca²⁺-uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca²⁺ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca²⁺ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca²⁺ microdomain could explain seemingly controversial results on mitochondrial Ca²⁺ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca²⁺ uptake facilitated by microdomains may shape cytosolic Ca²⁺ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca²⁺ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle.