Oligodendrocytes and Schwann cells are highly specialized glial cells that wrap axons with a multilayered myelin membrane for rapid impulse conduction. Investigators have recently identified axonal signals that recruit myelin-forming Schwann cells from an alternate fate of simple axonal engulfment. This is the evolutionary oldest form of axon-glia interaction, and its function is unknown. Recent observations suggest that oligodendrocytes and Schwann cells not only myelinate axons but also maintain their long-term functional integrity. Mutations in the mouse reveal that axonal support by oligodendrocytes is independent of myelin assembly. The underlying mechanisms are still poorly understood; we do know that to maintain axonal integrity, mammalian myelin-forming cells require the expression of some glia-specific proteins, including CNP, PLP, and MAG, as well as intact peroxisomes, none of which is necessary for myelin assembly. Loss of glial support causes progressive axon degeneration and possibly local inflammation, both of which are likely to contribute to a variety of neuronal diseases in the central and peripheral nervous systems.