This chapter reviews fatigue as a symptom, and explains some of its syndromes which include chronic fatigue syndrome and vital exhaustion. Prolonged or chronic fatigue is significantly less common than the symptom of fatigue, and there has been uncertainty about the existence of a chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME). Many studies demonstrate the close association between mood disorders, especially depressive illness, and CFS. Vital exhaustion comprises unusual fatigue, loss of energy, increased irritability and feelings of demoralisation. Apart from the stronger evidence for the importance of infections in the aetiology of fatigue more than depression, there are important pathophysiological differences as well. The hypothalamic-pituitary-adrenal (HPA) axis is down-regulated in CFS and up-regulated in melancholic depressive illness. CBT and graded exercise therapy are useful treatments of both mood disorders and CFS. The syndromes of fatigue and depression share symptoms, which leads to easy misdiagnosis and inflated comorbidity.