Aerobic metabolism is assumed to rely predominantly on glucose as fuel for the tricarboxylic acid (TCA) cycle and mitochondrial respiration. Hui et al. showed that lactate derived from the circulation can predominantly fuel the TCA cycle in most tissues. They investigated circulatory fluxes of metabolites through stable isotopic tracing in fed and fasted mice and found that, in both states, the flux of lactate was highest among all metabolites tested, including glucose. During the fasted state, glucose-derived carbons contributed to the TCA cycle mainly indirectly, via circulating lactate. Finally, in genetically engineered mouse models of lung and pancreatic cancer, circulating lactate was identified as the primary substrate for the TCA cycle. Overall, this study shows how aerobic energy production is decoupled from glycolysis, thereby allowing independent regulation of these processes across tissues.