Although axonal loss has been observed in demyelinated multiple sclerosis (MS) lesions, there has been a major focus on understanding mechanisms of demyelination. However, identification of markers for axonal damage and development of new imaging techniques has enabled detection of subtle changes in axonal pathology and revived interest in the neurodegenerative component of MS. Axonal loss is generally accepted as the main determinant of permanent clinical disability. However, the role of axonal loss early in disease or during relapsing-remitting disease is still under investigation, as are the interactions and interdependency between inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of MS.