The glucose analogue 18F-deoxyglucose allowed for the first time the ability to noninvasively probe and characterize the regional metabolism of glucose as a major fuel substrate of the human heart. Used with positron emission tomography, it became the tool for demonstrating the operation of metabolic processes, long before established in invasive or destructive experiments in animals, directly in the human myocardium. Clinical investigations with 18F-deoxy-glucose, combined with other radiotracers of the myocardium's substrate metabolism, showed the dependency of the heart's substrate selection on circulating levels of glucose, free fatty acid and insulin, and the operation of Randle's cycle in the human myocardium. Regional responses in substrate metabolism to the myocardial ischemia were now visualized entirely noninvasively as, for example, decreases in fatty acid usage and oxidation and oxygen consumption, but foremost as an increase in glucose use. Regional 18F-deoxyglucose uptake markedly in excess of myocardial blood flow in dysfunctional myocardium of patients after a myocardial infarction, with chronic coronary artery disease or with ischemic cardiomyopathy, soon became recognized as a hallmark of myocardial viability or potentially reversible contractile dysfunction. Defined as blood flow metabolism mismatch, this particular regional glucose uptake pattern identifies patients to be at high risk for cardiac events and, at the same time, to benefit most from surgical revascularization. The patterns predict a postrevascularization improvement in global left ventricular function and, even more important, in symptoms related to congestive heart failure and in long-term survival. 18F-deoxyglucose is now widely used with positron emission tomography and, more recently, with single photon emission computed tomography and radiotracers of myocardial perfursion for stratifying ischemic cardiomyopathy patients to the most efficacious treatment.