Among the constituent cell types of the multiple sclerosis (MS) plaque, the astrocyte has been the least considered as a player in the pathogenesis of the lesion. Traditionally, it has been assigned a secondary scarring role with little or no role in lesion formation or repair. However, the recent upsurge of interest in the demyelinating condition neuromyelitis optica (NMO) has resulted in NMO being identified as the first disease of myelin in which primary damage to astrocytes, resulting from a humoral immune response that forms against the water channel aquaporin-4, has been documented. This finding in NMO prompted us to re-examine data and material from cases of MS displaying active lesions. Our reappraisal revealed unambiguous early damage to perivascular astrocyte end-feet and to hypertrophic astrocytes in the adjacent parenchyma, but whether this was a primary event was difficult to evaluate due to concomitant edema and inflammation in these acute lesions. The astrocyte damage was long-lasting since resolving lesions displaying remyelination also showed defects in the integrity of the astrocytic covering around blood vessels. Analysis of our findings and of the astrocytic literature supports multiple roles for the astrocyte in the evolution of changes encountered in MS depending upon lesion stage and lesion topography. At variance with the somewhat inhibitory role of the astrocyte is the abundant and growing evidence for this cell to actively participate in both lesion development and repair. We propose that the unequivocal selective early involvement of the astrocyte in MS lesions may have therapeutic relevance. © 2013 Wiley Periodicals, Inc.