Cardiac health is dependent on the heart’s ability to utilize different substrates to support overall oxidative metabolism to generate ATP. Indeed, a loss in plasticity in substrate preference is characteristic of a variety cardiac diseases such as diabetic heart disease, in which fatty acid metabolism predominates, and dilated cardiomyopathy, in which glucose metabolism predominates. Because of the pleiotropic actions of myocardial substrate metabolism, a loss in plasticity in substrate preference can have detrimental effects well beyond impairment of energy production, including perturbations in various cell signaling pathways, alterations in cell growth, and decreased cell survival. Despite the rapid growth in our understanding of the relationship between altered myocardial metabolism and cardiac disease, many important questions remain. For example, what are the key determinants of changes in myocardial substrate use? When these changes do occur, to what extent are they adaptive or have the propensity to become maladaptive? And are these metabolic patterns of prognostic significance? Although transgenic models targeting vital aspects of myocardial substrate use are providing mechanistic insights into myocardial metabolic-functional relationships in various cardiac diseases, the relevance of the observed phenotypes to the corresponding human condition is frequently unclear. Likewise, applied genomics have identified numerous gene variants intimately involved in the regulation of myocardial substrate use, yet identifying all clinically relevant genetic variants remains elusive. As a consequence, there is an ever-growing demand for accurate noninvasive imaging approaches of myocardial substrate metabolism that provide links between the bench and the bedside. In this regard, radionuclide approaches have led the way. The most notable example of clinical applicability is the detection of ischemic but viable myocardium with positron emission tomography (PET) and 18F-fluorodexoglucose (FDG) for the treatment of patients with ischemic cardiomyopathy. In the subsequent discussion, advances in metabolic imaging using radionuclide approaches and their potential future applications …