Fatigue is the most common symptom of multiple sclerosis. 75%-90% of patients with multiple sclerosis report having fatigue, and 50%-60% describe it as the worst symptom of their disease. Fatigue is significantly associated with reduced quality of life and is also a major reason for unemployment, especially for patients with otherwise minor disability. The mechanisms underlying abnormal levels of fatigue in multiple sclerosis are poorly understood. To date, drug treatment has been only partially successful in alleviating fatigue, and effects vary widely from patient to patient. Amantadine and modafinil showed to be effective in the treatment of fatigue in some studies. Non-pharmacological management of fatigue in multiple sclerosis includes inpatient rehabilitation and endurance training. There is also evidence, that pulsing electromagnetic fields may improve fatigue associated with multiple sclerosis. This paper summarizes the recent literature on pathophysiology, diagnosis and therapy of the most common symptom of multiple sclerosis.