Excitation-contraction coupling is the process by which electrical activation is translated into contraction of a cardiac myocyte and thus the heart. In heart failure, expression, phosphorylation, and function of several intracellular proteins that are involved in excitation-contraction coupling are altered. The present review article summarizes central principles and highlights novel aspects of alterations in heart failure, focusing especially on recent findings regarding altered sarcoplasmic reticulum Ca2+ -leak and late Na+ -current without being able to cover all changes in full detail. These two pathomechanisms seem to play interesting roles with respect to systolic and diastolic dysfunction and may also be important for cardiac arrhythmias. Furthermore, the article outlines the translation of these novel findings into potential therapeutic approaches.