Integrated mechanisms of regulation of energy metabolism at cellular, tissue, and organ levels are analyzed from a systems biology perspective. These integrated mechanisms comprise the coordinated function of three cycles of mass and energy transfer and conversion: (1) the Randle cycle of substrate supply, (2) the Krebs cycle coupled with energy transformation in mitochondrial oxidative phosphorylation, and (3) the kinase cycles of intracellular energy transfer and signal transduction for regulation of energy fluxes. These cycles are extended and partially governed by information transfer systems like those linked to protein kinase signaling. In the heart, these cycles are closely related to the Ca2+ cycle during excitation–contraction coupling. According to the view of integrated metabolic cycles, the phosphocreatine/creatine kinase system represents a most important subsystem determining the efficiency of regulation of metabolic and energy fluxes in heart, brain, and oxidative skeletal muscles. It carries about 80 % of the energy flux between mitochondria and cytoplasm in heart. The substrate uptake, respiration rate, and energy fluxes are regulated in response to workload via phosphotransfer pathways and Ca2+ cycling. We propose integrated network mechanisms to explain the linear relationship between myocardial oxygen consumption and heart work output under conditions of metabolic stability (metabolic aspect of Frank–Starling’s law of the heart). The efficiency of energy transfer, force of contraction, and metabolic regulation of respiration and energy fluxes depend upon the intracellular concentration of total creatine, which is decreased in heart failure. The role of creatine, creatine kinase, and adenylate kinase phosphotransfer and AMP-activated protein kinase (AMPK) signaling systems and their interrelationship with substrate supply and Ca2+ cycles are analyzed. Finally, an introduction to the AMPK signaling network is provided with a particular emphasis on the heart in health and disease.