While fatigue and excessive daytime sleepiness may coexist in many medical, neurological, and primary sleep disorders, they are distinct clinical symptoms that have different etiologies and treatment strategies. Making the distinction between fatigue and sleepiness is crucial to the management of a variety of conditions. This chapter provides an overview of fatigue from the perspective of the general practitioner, neurologist, and sleep specialist, and summarizes recent research developments in the field, including neuroimaging in fatigue. Emphasis is placed on the evaluation of fatigue in patients with a variety of neurological conditions (including multiple sclerosis, basal ganglia disorders, and post-polio fatigue), medical disorders, and sleep disorders, as well as on chronic fatigue syndrome.