Oligodendrocytes are the myelin-forming cells of the central nervous system. Despite close relationship between oligodendrocyte and neuron, little is known about the exact role and nature of oligodendrocyte/axons interactions. We used an in vitro myelinating system to study axonal signals involved in myelination and showed: i) that only axons are myelinated, suggesting the existence of an axonal recognition signal and ii) that electrical activity seems necessary for myelination to proceed, as nerve influx blockade by tetrodotoxin strongly inhibits myelination. Moreover, myelinating oligodendrocyte appears to modulate axonal neurofilament phosphorylation. Knowledge of these reciprocal interactions may modify our physiopathological and therapeutical conceptions in human demyelinating diseases like multiple sclerosis.