Abstract: From the first stages of differentiation in the embryo to the end of life, energy substrate metabolism and function are inextricably linked features of the heart. The principle of energy substrate metabolism is simple. For a given developmental stage and for a given environment, the heart oxidizes the most efficient fuel on the path to ATP. The “multitasking” of energy substrate metabolism in the heart entails more than the generation of reducing equivalents for oxidative phosphorylation of ADP in the respiratory chain. In the postnatal heart, substrate switching and metabolic flexibility are features of normal function. In the stressed heart, metabolic remodeling precedes, triggers, and sustains functional and structural remodeling. This manuscript reviews the pleiotropic actions of metabolism in energy transfer, signal transduction, cardiac growth, gene expression, and viability. Examples are presented to illustrate that metabolic signals of stressed and failing heart are the product of complex cellular processes. An early feature of the maladapted heart is a loss of metabolic flexibility. The example of lipotoxic heart failure illustrates the concept of sustained metabolic dysregulation as a cause of contractile dysfunction of the heart. Thus, a paradigm emerges in which metabolic signals not only regulate fluxes through enzyme catalyzed reactions in existing metabolic pathways, but also regulate transcriptional, translational, and post‐translational signaling in the heart. As new insights are gained into metabolic adaptation and maladaptation of the heart, metabolic modulation may become an effective strategy for the treatment of heart failure.