Recent evidence suggests that energy substrate metabolism forms the link between gene expression and contractile function of the heart. This hypothesis draws on three seemingly unconnected observations, made in 1941 by three different investigators. The first gave rise to the concept of the dynamic nature of body constituents, the second to the concept of one gene for one enzyme, and the third to the concept of energy conservation in the phosphate bond of adenosine triphosphate (ATP), the "approximate P." The heart employs different mechanisms to adapt to acute and to sustained changes in energy demand. While acute changes in energy demand are met by the coordinated activation or inactivation of enzymes, chronic changes in energy demand are met by adjustments in the rate of "metabolic" gene expression which are often isoform specific. Transcriptional analysis by quantitative polymerase chain reaction (PCR) defines changes in energy substrate metabolism in response to an altered physiologic environment at the transcriptional level. The paradigm of cardiac hypertrophy and atrophy has revealed a surprisingly uniform and rapid response in cardiac gene expression including the reactivation of fetal metabolic genes. The physiologic consequences are revealed in a shift in substrate utilization from fatty acids to glucose. Clinical consequences include a change in metabolic gene expression of the failing human heart, including the downregulation of glucose transporters and the enzymes of fatty acid metabolism. Although it is possible to study regulation of metabolism at the level of gene expression, the complexities of the interactions between metabolic intermediates and transcription factors may be difficult to elucidate by simple reductionist approaches. A model of feedback/feedforward between genes and proteins is needed to explain the principle of reestablishing homeostatic control of metabolism as cellular and external environments change.