Fatigue is a common disabling symptom of multiple sclerosis (MS). It is often considered a state of exhaustion distinct from depressed mood or physical weakness. Fatigue can be assessed by either self-report scales or performance-based measures; however, neither method captures all features of fatigue. Fatigue in MS frequently leads to unemployment. It is associated with a sense of loss of control over one's environment, low positive affect, psychological distress and neurological impairment. To date there is no reproducible neuroimaging marker or biological correlate that has been identified. Proposed pathological mechanisms of fatigue in MS include neuronal factors such as dysfunction of premotor, limbic, basal ganglia or hypothalamic areas; disruption of the neuroendrocrine axis leading to low arousal; alteration in serotoninergic pathways; changes in neurotransmitter levels; and altered CNS functioning caused by a disruption of the immune response. Treatment of fatigue is best approached in a multidisciplinary fashion that incorporates nonpharmacological interventions as well as medication. Amantadine and modafinil are among the most commonly used medications for fatigue associated with MS. Both medications have been studied with positive results in controlled clinical trials. Additional research towards measurement and pathogenesis of fatigue will hopefully lead to improved therapies.