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Fatigue is a common symptom in multiple sclerosis (MS). As fatigue includes a variety of aspects, its treatment is best approached in a multidisciplinary fashion that includes nonpharmacological interventions and medications. In individuals with mild fatigue non-pharmacological treatment including yoga, aerobic exercises, cooling therapy and energy conservation techniques might be considered. Several pharmacological treatments for patients with significant fatigue have proved to be effective. Among these agents, amantadine and aminopyridines are the most frequently used. More recently also aspirin and carnitine have been used to treat MS fatigue but they need to be confirmed in larger studies.