Multiple sclerosis (MS) is a chronic, autoimmune, demyelinating disease of the central nervous system. Fatigue is a very common clinical entity in individuals with multiple sclerosis, with a prevalence ranging from 52% to 88% during the course of the disease. Fatigue significantly impacts the quality of life of patients and is considered to be one of the most disabling symptoms of the disease. Fatigue is defined as an overwhelming sense of exhaustion and lack of mental and physical energy that is not proportional to objective physical or cognitive exertion. The complex etiology and pathogenesis of fatigue in MS involves systemic mechanisms (immune system dysregulation), central mechanisms (the hypothalamic-pituitary-adrenal axis, energy imbalance, neurotransmitters, structural and functional neurological changes), and peripheral mechanisms (abnormal neuromuscular signal transmission). The interaction of these mechanisms leads to a wide range of symptoms. The diagnosis of fatigue relies on subjective methods, assessing the level of fatigue using specific scales in the form of patient questionnaires. Objective methods involve measuring various parameters before and after testing patients' performance on specific physical or cognitive tasks. Less specific scales are used to determine the impact of fatigue syndrome on patients' daily lives and their quality of life. Due to the wide range of symptoms, it is important to differentially diagnose fatigue from the other possible conditions in individuals with MS, such as depression or cognitive disorders. Therapeutic approaches involve pharmacological and non-pharmacological methods with varying degrees of success. Pharmacological methods include usage of medications such as amantadine, modafinil, antidepressants, fampridine, disease-modifying drugs, L-carnitine, and vitamin D. Non-pharmacological methods include complementary and alternative medicine, physiotherapy and rehabilitation involving physical activity, exercise and the application of physical agents, psychological therapy, education and non-invasive brain stimulation techniques.