Astrocyte activation has been linked to neurodegeneration in conditions such as multiple sclerosis (MS); however, the molecular mechanisms involved are unclear. The authors found that the enzyme that synthesizes lactosylceramide (LacCer) is upregulated in astrocytes in experimental autoimmune encephalomyelitis (a mouse model of MS) and in clinical MS lesions. LacCer was found to promote astrocyte activation and to control the transcription of genes related to neuroinflammation and neurodegeneration. Thus, upregulation of LacCer production in astrocytes may contribute to disease pathogenesis in inflammatory CNS conditions.