Clearly, the use of functional neuroimaging for the study of fatigue is in its infancy. Relatively few studies focusing on fatigue using functional neuroimaging techniques have been published, and the few that exist focus primarily on persons with MS and CFS. The vast majority of these studies have examined self-reported fatigue, an approach that benefits from ease of administration but suffers from significant difficulties in interpretation. For example, we know that self-reported fatigue most often correlates with the degree of psychopathology.1 We also know that with more than 100 years of inquiry, self-reported fatigue does not correlate with objective measures of fatigue. As such, when functional imaging studies show a relationship between self-reported fatigue and activities in distinct areas of the brain, one must remain cautious about the interpretation of these results. A more recent approach in the functional imaging literature is to assess fatigue behaviorally during scanning and relate such objective measures of fatigue with cerebral activation. Although this is a new and novel approach, it remains unclear if this approach of operationally defining fatigue behaviorally will be a more valid paradigm in understanding the elusive construct of fatigue. Although fatigue is extraordinarily common as a symptom in many neurologic and psychiatric diseases, little is known about its precise mechanism. Chaudhuri and Behan hypothesized that the nonmotor functions of the basal ganglia play a key role in central fatigue. Specifically, they posit that fatigue is due to "alterations in the normal flow of sequential activation within the basal ganglia system affecting the neural integrator and the cortical feedback by the associated loop of the striato-thalamo-cortical fibers is a possible mechanism of central fatigue ." (p40). Therefore, other regions interacting with the basal ganglia may also contribute to fatigue, including the frontal cortex, thalamus, and the amygdala. In general, the functional imaging studies reviewed in this article tend to generally support the suggestion that damage to cortical-subcortical circuitry might be to blame for fatigue as well. If indeed fatigue is associated with functional impairment in a cortical-subcortical circuitry, it might be that studies that have examined structural damage (eg, total lesion load throughout the brain) may simply not provide the sensitivity required to detect a relationship between fatigue and pathology. After more than 100 years of frustration, it appears that functional neuroimaging techniques promise to provide an exciting potential for significant advances in our elusive understanding of the brain mechanisms associated with fatigue in clinical populations.