How axonal damage, a major prognostic factor of multiple sclerosis disability progression, is induced, is likely to be multifactorial. Whereas axonal injury has been identified as a consequence of myelin loss, the possibility of an additional direct damage is also suggested. In this context, recent data have highlighted the nodal and perinodal axonal domains of the myelinated neurons as potential targets of the disease process, opening new perspectives in multiple sclerosis pathophysiology.