The heart is a biological pump that converts chemical to mechanical energy. This process of energy conversion is highly regulated to the extent that energy substrate metabolism matches energy use for contraction on a beat-to-beat basis. The biochemistry of cardiac metabolism includes the biochemistry of energy transfer, metabolic regulation, and transcriptional, translational as well as posttranslational control of enzymatic activities. Pathways of energy substrate metabolism in the heart are complex and dynamic, but all of them conform to the First Law of Thermodynamics. The perspectives expand on the overall idea that cardiac metabolism is inextricably linked to both physiology and molecular biology of the heart. The article ends with an outlook on emerging concepts of cardiac metabolism based on new molecular models and new analytical tools.© 2016 American Physiological Society. Compr Physiol 6: 1675-1699, 2016.