Narcolepsy with associated cataplexy is a disabling sleep disorder that affects 0.05% of the general population. Whereas narcolepsy-cataplexy is largely considered as etiologically homogeneous, hypersomnias without cataplexy represent a very heterogeneous group of clinical entities that must be thoroughly explored before final diagnosis of narcolepsy is given. A typical treatment for narcolepsy-cataplexy associates amphetamine-like stimulants for sleepiness and antidepressant therapy for abnormal rapid eye movement sleep (cataplexy, sleep paralysis, and hypnagogic hallucinations). This treatment is purely symptomatic and involves activation of central dopaminergic and adrenergic activity respectively. Genetic research indicates a role for the immune system rather than abnormalities in monoaminergic or cholinergic systems as the primary cause for narcolepsy. Human narcolepsy is tightly associated with HLA-DQB1*0602; canine narcolepsy is linked with a DNA segment with high homology with the human immunoglobulin mu-switch segment, and the onset of canine narcolepsy is associated with increased microglial expression of major histocompatibility complex DQ and DR molecules. Taken together with the lack of direct evidence for an autoimmune process in narcolepsy, these results may suggest the existence of novel neuroimmune interactions in narcolepsy and open new perspectives in the treatment of this disabling disorder.