The prevalence of coronary artery disease and heart failure is increasing in modern industrialized countries, fueling the search for novel therapies. Because metabolism and function in the heart are inextricably linked, energy substrate metabolism has provided a potential target for novel therapies and the development of technologies to image myocardial metabolism has been crucial in establishing new therapeutic approaches. Nuclear imaging probes have been used to successfully evaluate aerobic fatty acid metabolism, anaerobic glucose metabolism, and oxidative metabolism and can be used for the accurate, sensitive, and physiological evaluation of therapeutic effects. More recently, with the advent of stem-cell technologies, imaging approaches have been employed to track the fate of stem cells and to monitor the success of these treatments. In the future, our ability to image myocardial metabolism is likely to assist the development of other new therapies to improve the function of the failing heart.