Nature Reviews Neurology, Published online: 04 April 2025; doi:10.1038/s41582-025-01081-yAutoimmunity in multiple sclerosis (MS) is generally considered to be directed against components of myelin or oligodendrocytes. However, this Perspective argues that an immune attack on the ion and water homeostasis machinery in astrocytic endfeet is the primary event in MS and that myelin damage results from astrocyte dysfunction.