Cardiac energy substrate selection is a dynamic balance influenced by developmental, physiological, and pathological cues. In the fetal heart, glucose oxidation is favored, whereas FA oxidation serves as the major ATP-generating pathway in the adult myocardium. Significant shifts in substrate preference occur in response to dietary (insulin) and physiological (exercise) stimuli. Certain pathophysiological contexts, such as hypertrophy and ischemia, drive metabolism toward glucose utilization, whereas in uncontrolled diabetes, the heart utilizes FAs almost exclusively. In some cases, as in early response to pressure overload–induced hypertrophy, these metabolic shifts are thought to be protective. Alterations in activity or expression of nuclear receptors (PPARs and ERRs) and PGC-1α mediate these shifts in energy substrate utilization.