For many years, loss of myelin was considered to be the major cause of neurological dysfunction in multiple sclerosis (MS), a chronic inflammatory, demyelinating disease of the central nervous system. This ‘myelinocentric’ view of MS was revised recently, after recognition that axonal damage, rather than demyelination, provides a better correlate to clinical symptoms. Nonetheless, current views of MS pathogenesis remain focused on the role of myelin-specific autoimmunity, and the potential contribution of autoimmune responses to axonal and neuronal antigens is ignored. Drawing on experience gained from work with other neurodegenerative diseases, we hypothesize that autoimmunity, particularly pathogenic antibodies to neuronal and axonal antigens, plays a significant role in the development of axonal pathology in MS. This concept offers a new perspective of disease pathogenesis and therapeutic approaches to prevent irreversible axonal loss and chronic disability in MS.