Energy in the form of ATP is supplied from the oxidation of fatty acids and glucose in the adult heart in most species. In the fetal heart, carbohydrates, primarily glucose and lactate, are the preferred sources for ATP production. As the newborn matures the contribution of fatty acid oxidation to overall energy production increases and becomes the dominant substrate for the adult heart. The mechanisms responsible for this switch in energy substrate preference in the heart are complicated to identify due to slight differences between species and differences in techniques that are utilized. Nevertheless, our current knowledge suggests that the switch in energy substrate preference occurs due to a combination of events. During pregnancy, the fetus receives a constant supply of nutrients that is rich carbohydrates and poor in fatty acids in many species. Immediately after birth, the newborn is fed with milk that is high in fat and low in carbohydrates. The hormonal environment is also different between the fetal and the newborn. Moreover, direct subcellular changes occur in the newborn period that play a major role in the adaptation of the newborn heart to extrauterin life. The newborn period is unique and provides a very useful model to examine not only the metabolic changes, but also the effects of hormonal changes on the heart. A better understanding of developmental physiology and metabolism is also very important to approach certain disorders in energy substrate metabolism.