During fetal life, myocardial ATP is derived predominantly from glycolysis and lactate oxidation. Following birth, a rapid maturational increase in fatty acid oxidation occurs along with a decline in glycolytic and lactate oxidative rates, thus changing the major source of myocardial ATP production. This shift in energy substrate preference occurs in response to changes in the circulating substrate content of newborn plasma with the onset of suckling, and is also due to alterations in circulating levels of hormones, such as insulin and glucagon. Important changes in subcellular regulatory mechanisms of both fatty acid and carbohydrate metabolism in the heart also characterize this response. This review deals with recent advances in the understanding of these subcellular mechanisms which regulate this important shift in myocardial energy metabolism, with particular emphasis on the molecular events occurring in the heart during the transition from fetal to newborn life.