<p>Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. The chain of events that results in demyelinating lesions is not understood, although most theories assume a primary immune attack on myelin. However, the glial cell adhesion molecule GlialCAM, which forms part of a protein complex in astrocytic endfeet that is crucial for brain ion and water homeostasis, was recently identified as a target for autoimmunity in patients with MS. This complex also includes the astrocytic transmembrane protein MLC1, the water channel aquaporin 4 (AQP4) and the potassium channel KIR4.1. Autoimmunity against AQP4 underlies another demyelinating disorder, neuromyelitis optica, and autoimmunity against KIR4.1 has been implicated in a subtype of MS. Genetic defects in any of these proteins cause leukodystrophies with disruption of brain ion and water homeostasis, which is regulated by astrocytes and secondarily affects myelin. In this Perspective, we argue that an immune attack on the ion and water homeostasis machinery in astrocytic endfeet, rather than directly on myelin, is the primary event in MS and that myelin damage is a consequence of astrocyte dysfunction. This hypothesis is supported by pathological studies on tissue from people with MS and has important implications for disease models and therapy targets.</p>