Narcolepsy is characterized by excessive daytime sleepiness and abnormal rapid eye movement sleep. It affects about 0.05% of the Caucasian population. Human narcolepsy involves the interaction of environmental factors with a specific immunogenetic background. It is tightly associated with a major histocompatibility complex allele, human leukocyte antigen (HLA) DQB1^*0602. Genetic factors other than HLA are also involved. In contrast, narcolepsy in Dobermans is transmitted as a single autosomal recessive trait. This canine narcolepsy gene is unlinked to the major histocompatibility complex class II but co-segregates with a DNA segment with high homology to the human immunoglobulin μ-switch sequence, further suggesting immunopathology in narcolepsy. However, attempts to demonstrate that narcolepsy is an autoimmune disease have been unsuccessful. Narcolepsy is treated with antidepressants for rapid eye movement sleep-related symptoms and with amphetamine-like stimulants for sleepiness. Pharmacological studies using narcoleptic canines indicate that monoaminergic and cholinergic systems are involved in the pathophysiology of narcolepsy. Dopaminergic uptake mechanisms and D₂₍₃₎ autoreceptors are involved in the control of alertness, whereas adrenergic uptake mechanisms, α-1 and α-2/dopaminergic D₂₍₃₎ receptors, are involved in the control of cataplexy, suggesting that amphetamine-like stimulants act via the dopaminergic system and that antidepressants exhibit their anticataplectic effects via the adrenergic system. Local drug perfusion studies indicate that D₂₍₃₎ agonists in the ventral tegmental area induce cataplexy and sleepiness in narcoleptic dogs but not in control dogs. Furthermore, perfusion of M₂ agonists in the pontine reticular formation and the basal forebrain induces cataplexy in narcoleptic dogs. Extracellular single-unit and acetylcholine measurement studies suggest that basal forebrain cholinoceptive sites mediate the emotional trigger for cataplexy. Although narcolepsy does not seem to be a classical autoimmune disease, concomitant increases in microglial HLA class II expression with the development of the disease occur in canine narcolepsy. A neuroimmune-related process at an early age is thus likely to contribute to the neurochemical imbalance seen in narcolepsy. NEUROSCIENTIST 4:133–143, 1998