Skeletal muscle is the main insulin-sensitive tissue for postprandial glucose disposal and for the oxidation of glucose- and lipid-based fuels. Forkhead box (FOXO) proteins play a role in the regulation of energy metabolism. However, the role of specific FOXO isoforms in metabolic homeostasis in skeletal muscle remains unclear. Lundell et al. reveal that FOXO1 and FOXO3 transcriptional activity is necessary for the regulation of glucose handling and control of inflammatory signaling in mature skeletal muscle.