The diagnosis of multiple sclerosis (MS) and the consequent therapeutic choices have been rendered considerably easier by the advent of magnetic resonance imaging; however, conventional MR images alone do not fully explain the clinical severity of MS patients; this poor correlation between clinical and radiological findings has been referred to as the clinico-radiological paradox. Histological studies and non-conventional MRI have shown that MS alterations are not confined to white matter lesions, but may be found in both normal-appearing white matter (NAWM) and in grey matter. It has been established that irreversible tissue damage in MS leads to disability; it should, however, be borne in mind that the clinical outcome in MS patients is the result of a balance between the severity of damage to the central nervous system and the effectiveness of the repair and recovery mechanisms in such patients. These plastic changes are believed to underlie the changes in functional activity that can be observed during functional magnetic resonance (fMRI) studies. In patients with MS, functional brain reorganization mainly consists of an increase, if compared with healthy subjects, in the extent of activation in the affected brain areas, as well as the recruitment of additional brain areas. These findings have been interpreted as adaptive mechanisms that allow normal performance despite neural damage or loss. However, recent studies suggest that brain functional activity changes may merely be an epiphenomenon due to neuronal damage.