Multiple sclerosis (MS) is an inflammatory demyelinating disease that is considered by many people to have an autoimmune aetiology. In recent years, new data emerging from histopathology, imaging and other studies have expanded our understanding of the disease and may change the way in which it is treated. Conceptual shifts have included: first, an appreciation of the extent to which the neuron and its axon are affected in MS, and second, elucidation of how the neurobiology of axon-glial and, particularly, axon-myelin interaction may influence disease progression. In this article, we review advances in both areas, focusing on the molecular mechanisms underlying axonal loss in acute inflammation and in chronic demyelination, and discussing how the restoration of myelin sheaths via the regenerative process of remyelination might prevent axon degeneration. An understanding of these processes could lead to better strategies for the prevention and treatment of axonal loss, which will ultimately benefit patients with MS.