The diagnosis of chronic fatigue syndrome (CFS) is made difficult by the absence of specific biomedical markers, and depends primarily on determining whether subjective information provided by the patient meets the clinical case definition of this syndrome. Reported cognitive difficulties and/or complaints of headache may instigate referral for brain imaging. This article will discuss the value of neuroimaging in evaluating CFS, specifically reviewing studies that (1) used static magnetic resonance imaging (MRI) to assess structural abnormalities; and (2) assessed regional cerebral blood flow (rCBF) via detection of Tc-99m hexamethylpropyl-eneamine oxime distribution by single-photon emission computed tomography (SPECT). Future research design considerations are explored including (1) the utilization of positron emission tomography (PET) and other emerging neuroimaging technologies; and (2) methodological concerns, i.e., the influence of psychopathology (such as depression) and neurologic disease (such as multiple sclerosis) as possible confounding factors.