Fatigue is one of the most common symptoms of multiple sclerosis (MS). It concerns almost all patients, and in approximately 50% of cases it is a major symptom. It may occur in cases of patients with little neurological symptoms and significantly affect the quality of life. Pathophisiology of fatigue is unknown. The role of various mechanisms has been suggested, including the hypothalamic-pituitary-adrenal (HPA) axis disfunction, effect of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) on glutaminergic transmission, disturbances of astroglia metabolism and decreased levels of neuro-transmitters noradrenalin and serotonin. The diagnosis of fatigue syndrome is based on anamnesis, physical examination, screening laboratory tests and exclusion of depression or additional organic conditions (anaemia, cardiovascular disorders, kidney diseases or hypothyroidism). Treatment of fatigue is complicated and ineffective. Pharmacological treatment leads to slight improvement. Many attempts of using medications (including Amantadine, Modafinil, Pemoline) gave contradictory results. Step-by-step physical exercise programs has proven to be more effective. Physical activity, rehabilitation, psychotherapy and avoidance of factors which may increase fatigue such as fever, anxiety, depression, pain, sleep disturbances, as well as some drugs like opiates and benzodiazepines, are important.