Fatigue is the most commonly reported and most debilitating of post-polio sequelae affecting the >1.8 million North American polio survivors. Post-polio fatigue is characterized by subjective reports of difficulty with attention, cognition, and maintaining wakefulness. These symptoms resemble those reported in nearly 2 dozen outbreaks of post-viral fatigue syndromes (PVFS) that have recurred during this century and that are related clinically, historically, anatomically, or physiologically to poliovirus infections. This article reviews recent studies that relate the symptoms of post-polio fatigue and chronic fatigue syndrome (CFS) to clinically significant deficits on neuropsychologic tests of attention, histopathologic and neuroradiologic evidence of brain lesions, impaired activation of the hypothalamic–pituitary–adrenal axis, increased prolactin secretion, and electroencephalogram (EEG) slow-wave activity. A possible common pathophysiology for post-polio fatigue and CFS, based on the Brain Fatigue Generator Model of PVFS, and a possibile pharmacotherapy for PVFS based on replacement of depleted brain dopamine, will be described.