Recent studies employing functional neuroimaging provide new insights into the elusive construct of fatigue. Studies have been conducted primarily in persons with multiple sclerosis (MS) and chronic fatigue syndrome (CFS). These studies outline the key role of the basal ganglia and frontal lobes in understanding the neural mechanisms associated with fatigue. The lack of a relationship between self-reported fatigue and objectively measured fatigue is outlined, and new functional imaging paradigms may lead to significant advances in relating cognitive fatigue to functional cerebral activity.