Recently it has become clear that the neuronal compartment plays a more important role than previously thought in the pathology of multiple sclerosis. Apart from demyelination, neuronal pathology is apparently largely responsible for the brain atrophy that can be observed early on and throughout the course of the disease. The loss of axons and their neurons in the course of chronic neuroinflammation is a major factor determining long-term disability in patients. The actual steps leading from immune attack against the myelin sheath to neuronal damage are not yet fully clear. Here we review key findings about direct axonal damage processes, demyelination-related neuronal pathology and cell-body pathology, the major pathologic correlates that underlie brain atrophy in MS.