Fatigue is a common, debilitating and often underestimated symptom in patients with multiple sclerosis (MS). The exact pathophysiological mechanism of fatigue in MS is still unknown. However, there are many theories involving different immunological, metabolic and inflammatory mechanisms of fatigue. Owing to the subjective nature of this symptom, its diagnosis is still very limited and is still based only on diagnostic questionnaires. Although several therapeutic agents have been used in the past to try to influence fatigue in MS patients, no single effective approach for the treatment of fatigue has yet been found. This review article aims to provide the reader with information on the current theories on the origin and mechanism of fatigue in MS, as well as diagnostic procedures and, finally, current therapeutic strategies for the management of fatigue in MS patients.