Fatigue is an overwhelming sense of tiredness or lack of energy, affecting both mental and physical domains. Fatigue is reported by about 50% of patients with multiple sclerosis (MS), and may be independent from depressed mood or weakness. Recently, the importance of distinguishing between subjective complaint and objective signs of fatigue has been emphasized, since the self-reported increase of subjective cognitive fatigue may not be related to a decline of cognitive performances. There is a general consensus that fatigue in MS is a central phenomenon, related to several factors. Neurophysiological studies revealed an impairment of volitional drive to the descending motor pathways and functional imaging studies indicated a selective involvement of frontal cortex and basal ganglia. Thus, the physiopathology of fatigue may rely on dysfunction of circuits involving thalamus, basal ganglia, and frontal cortex, which, affected by the MS lesions or disturbed in their function by the products of inflammation, could be the substrate of fatigue. The abnormal subjective fatigue observed in MS and perhaps in other neurological disorders could be due to a higher brain working load required to perform a given mental or physical activity, or to an internal overestimation of such load.