Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are closely related illnesses of uncertain etiology. This article reviews the research literature on these biobehavioral conditions, with an emphasis on explanatory models, clinical evaluation of comorbid psychiatric disorders, assessment of stress factors, pharmacologic and alternative therapies, and cognitive-behavioral treatment studies. Furthermore, clinical protocols suitable for professional practice are presented based on an integration of the authors' clinical observations with published data. The article concludes with the recognition that mental health professionals can offer substantial help to these patients. © 2001 John Wiley & Sons, Inc. J Clin Psychol 57: 433–455, 2001