The cardiovascular system operates under a wide scale of demands, ranging from conditions of rest to extreme stress. How the heart muscle matches rates of ATP production with utilization is an area of active investigation. ATP-sensitive potassium (KATP) channels serve a critical role in the orchestration of myocardial energetic well-being. KATP channel heteromultimers consist of inwardly-rectifying K+ channel 6.2 and ATP-binding cassette sulfonylurea receptor 2A that translates local ATP/ADP levels, set by ATPases and phosphotransfer reactions, to the channel pore function. In cells in which the mobility of metabolites between intracellular microdomains is limited, coupling of phosphotransfer pathways with KATP channels permits a high-fidelity transduction of nucleotide fluxes into changes in membrane excitability, matching energy demands with metabolic resources. This KATP channel-dependent optimization of cardiac action potential duration preserves cellular energy balance at varying workloads. Mutations of KATP channels result in disruption of the nucleotide signaling network and generate a stress-vulnerable phenotype with excessive susceptibility to injury, development of cardiomyopathy, and arrhythmia. Solving the mechanisms underlying the integration of KATP channels into the cellular energy network will advance the understanding of endogenous cardioprotection and the development of strategies for the management of cardiovascular injury and disease progression.