This review will update current views of the physiopathology and treatment of fatigue in multiple sclerosis. Fatigue is a common symptom in multiple sclerosis, being reported by about a third of the patients. For many of them it is the most disabling symptom, with negative consequences on working activity and daily life. There are no objective measures of fatigue which is essentially based on subjective complaints. Even if fatigue may be influenced by motor disturbances and depression, it is largely independent from both. Peripheral mechanisms, such as muscular disuse and deconditioning, joint abnormalities and metabolic changes of muscular fibers, have very little role in multiple sclerosis fatigue. All the available data indicate that fatigue is a 'central' phenomenon, due to multiple causes. Neurophysiological studies revealed an impairment of volitional drive to the descending motor pathways and functional imaging studies fund a selective involvement of frontal cortex and basal ganglia. Therefore, a dysfunction of the circuits between thalamus, basal ganglia and frontal cortex, affected by the multiple sclerosis lesions and/or disturbed in their function by the products of inflammation could be the substrate of fatigue. No specific treatments are available - management strategies include medications, exercise and behavioral therapy - in most cases a combined approach is suitable. Enhancers of vigilance, like amantadine and modafinil, were shown to be effective in class I and II trials, however their effects are modest. Aminopyridines may indirectly influence fatigue by reducing nerve conduction block in motor fibers. Some recent studies suggest the positive effects of drugs on fatigue may be via reducing the inflammatory activity, such as for glatiramer acetate.