1. Chronic fatigue syndrome (CFS) is characterized by a new onset of significant fatigue for a period of six months or longer usually following an infection, injury or period of high stress. 2. The exact etiology of CFS is not known and a diagnostic test is not available. Hence, the diagnosis is made by exclusion of other explanations for the patient's symptoms and by meeting the CDC research case definitions. Early studies supported an infectious or immune dysregulation hypothesis for the pathophysiology of CFS. 3. Subsequent studies documented that neurological, affective and cognitive symptoms also occur at high rates in CFS patients. Neuropsychological, neuroendocrine studies and brain imaging have now confirmed the occurrence of neurobiological abnormalities in most patients with CFS. 4. In this article, the authors review these findings in relation to the clinical neurobiology of CFS and their potential relevance to biological psychiatry.