Myelinating glial cells are well-known to insulate axons and to speed up action potential propagation. Through adjustments in the axonal coverage with myelin, myelin sheath thickness and possibly nodal/internode length oligodendrocytes are involved in fine-tuning the brain's computational power throughout life. Be it motor skill learning or social behaviors in higher vertebrates, proper myelination is critical in shaping brain functions. Neurons rely on their myelinating partners not only for setting conduction speed, but also for regulating the ionic environment and fueling their energy demands with metabolites. Also, long-term axonal integrity and neuronal survival are maintained by oligodendrocytes and loss of this well-coordinated axon–glial interplay contributes to neuropsychiatric diseases. Better insight into how myelination and oligodendrocyte functions are constantly fine-tuned in the adult CNS, which includes sensing of neuronal activity and adjusting glial metabolic support, will be critical for understanding higher brain functions and cognitive decline associated with myelin abnormalities in the aging brain.