Investigations of functional interactions among axons and glia over the last decade have revealed the extent and complexity of glial-neuronal and glial-glial communication during development, adult function and recovery from injury. These data have profound implications for the understanding of central nervous system (CNS) disorders, which until recently, have been classified as either neuronal or glial diseases. Re-evaluation of the pathological processes in a number of conditions has clearly shown involvement of both neurons and glia in early pathology. In multiple sclerosis (MS), the myelin sheath has traditionally been regarded as the primary target. However, recent evidence has clearly demonstrated axonal damage in new lesions. We have addressed the question of the role of axonal pathology in early MS by using well-characterized murine models for the relapsing-remitting (RR) or the primary progressive (PP) forms of the disease. We performed a histopathological survey of the CNS, following induction of the disease, to determine the timing of appearance, as well as the development of lesions. Then we analysed the relationship between inflammation, demyelination and axonal damage together with responses from astrocytes and microglia in each model from the earliest evidence of inflammation. We found that axonal damage begins well ahead of the appearance of motor symptoms. Pathology appears to be more closely related to the degree of inflammation than to demyelination. We also show that early astrocyte responses and the degree of axonal loss are markedly different in the two models and relate to the severity of pathology. These data support the now widely accepted hypothesis that axonal damage begins early in the disease process, but also suggest modulation of axonal loss and disease progression by the astrocytic response.