As long as no causal treatment is available for multiple sclerosis (MS), and as long as only some patients with MS respond to immunomodulators, symptomatic treatment is of paramount importance. Fatigue is the most common symptom of MS and is associated with a reduced quality of life. It is described as the worst symptom of their disease by 50-60% of patients. The first step in managing MS-related fatigue is identifying and eliminating any secondary causes. Primary fatigue syndrome can be alleviated with drug treatment in many cases. Modafinil has been shown to be effective in some studies, and amantadine is an alternative for patients who do not respond to or cannot tolerate modafinil. The nonpharmacological management of fatigue in MS includes inpatient rehabilitation and aerobic endurance exercise. This article describes the pathophysiology, diagnosis and treatment of MS-related fatigue--the most common symptom of MS.