Multiple (MS) sclerosis is a chronic inflammatory demyelinating disease of the central nervous system with the pathological hallmarks of inflammation, demyelination, axon loss and gliosis. In the initial relapsing-remitting phase of the disease, the inflammatory-demyelinating component seems to predominate, whereas the progressive disease appears to be characterized by a neurodegenerative component leading to extensive neuroaxonal damage in the MS brain. Axon loss most likely determines the persistent neurological deficit in progressive MS. Recent studies pointed out that axon damage occurs early in the disease and during lesion development. Two different phases of axon degeneration were characterized, the first occurring during active myelin breakdown and the second in chronic demyelinated plaques in which the naked axon seems more susceptible to further damage. The exact mechanisms and effector molecules of axonal degeneration, however, are not yet defined, and an axon-protective therapy has not yet been established.