Fatigue, defined as subjective lack of energy to start and continue any activity without any connections with depression and muscular weakness, is one of the most common and troublesome symptoms of multiple sclerosis (MS). It concerns almost all patients, and in approximately half of them it is a major symptom. It may occur in cases of patients with little neurological symptoms and significantly affect the quality of life. In spite of intensive researches in last years pathophysiology of fatigue syndrome has not been enough recognized. The role of various mechanisms has been suggested: local prefrontal cortex and basal ganglia atrophy, changes in activity of B lymphocytes, disturbances of glutaminergic transmission caused by proinflammatory cytokines (TNF-α, IL-1β and IL-6), hypothalamic-pituitary-adrenal axis dysfunction, disturbances of astroglia metabolism with dehydroepiandrosteron (DHEA) decreased level and decreased levels of neurotransmitters noradrenaline and serotonin as well. The diagnosis of fatigue syndrome is based on anamnesis,physical examination, screening laboratory tests and evaluation by means of scales, for example Fatigue Severity Scale (FSS), Modified Fatigue Impact Scale (MFIS). The necessary condition is to exclude depression or additional organic conditions (anaemia, cardiovascular disorders, kidney diseases or hypothyroidism). Treatment of fatigue is not sufficiently effective. Pharmacological treatment leads to slight improvement although recent clinical trials with modafinil and fampridine have given promising results. Beneficial influence of physical exercises, cryotherapy and magnetotherapy has been observed. What may help in therapy is emotional support, cognitive-behavioural therapy and psychotherapy as well as avoidance of factors which may increase fatigue such as fever, anxiety, depression, pain, sleep disturbances, and also some drugs like opiates and benzodiazepines.