Kleine-Levin syndrome (KLS) is a rare neurological disorder primarily affecting young subjects. The first episode usually begins within a few hours, with patients becoming extremely tired, generally after an identifiable triggering event, such as a banal infection in most cases, alcohol intake, or a head trauma. The symptomatic periods involve hypersomnia, and cognitive, behavioral and psychological problems, and last from two days to several weeks. The most difficult differential diagnoses are psychiatric disorders (psychosis and depression), hence many patients are sent to the psychiatric department before the diagnosis of KLS is made. Recent methods of investigation such as SPECT indicate that the brain dysfunction could be larger than expected, and would encompass both cortical and subcortical (and especially thalamus and hypothalamus) areas. This general picture and the fluctuating symptoms in KLS are consistent with the possibility of an autoimmune mediation of the disorder.