Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are medically unexplained syndromes that can and often do co-occur. For this reason, some have posited that the two are part of the same somatic syndrome--examples of symptom amplification. This hypothesis would suggest that few differences exist between the two syndromes. To evaluate this interpretation, we have searched the literature for articles comparing CFS to FM, reviewing only those articles which report differences between the two. This review presents data showing differences across a number of parameters--implying that the underlying pathophysiology in CFS may differ from that of FM. We hope that our review encourages other groups to look for additional differences between CFS and FM. By continuing to preserve the unique illness definitions of the two syndromes, clinicians will be able to better identify, understand and provide treatment for these individuals.