Noninvasive positron emission tomography (PET)-based studies of myocardial blood flow and substrate metabolism characterized the human heart as an organ fully integrated with the general function of the human body. Cardiac energy demands are tightly coupled to peripheral needs in oxygen and, in turn, govern changes in myocardial blood flow and substrate supply. Substrate selection and utilization depend largely on substrate availability and, hence, on concentrations of fuel substrate in blood. Endocrine and neuronal factors together with regional transport processes modulate and fine tune regional rates of substrate utilization. Manipulation of substrate availability as for example through dietary or pharmacologic maneuvers offer a means to probe regional substrate interactions, to demonstrate shifts in substrate selection between free fatty acid and glucose and, hence, to confirm the operation of regulatory mechanisms established previously in animal experiments. In abnormal states, local factors modulate the generally integrated responses and synchronize regional substrate utilization and metabolism with regional needs. Diminished substrate delivery in chronic low flow conditions is matched by a down regulation in regional contractile function possibly as an energy saving measure, together with a decline in oxidative metabolism as evidenced by reduced oxidation of 11C-palmitate and delayed turnover of 11C-acetate. Activation of rate controlling enzymes together with enhanced transmembraneous transport systems represent flux generating steps for enhanced regional glucose consumption possibly as a means for reducing oxygen needs and at the same time, preserving cellular homeostasis. PET identifies such regional metabolic adjustments as regional increases in 18F-deoxyglucose uptake as a clinically useful hallmark of myocardial viability. Regional glucose utilization in this case no longer fully responds to general control mechanisms of substrate selection but is modified by local factors or, ultimately may become part of a local microsystem as a means of protection against potentially deleterious consequences of disease.