Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy. Available treatments of narcolepsy include stimulants and antidepressants but the recent discovery of orexin/hypocretin deficiency in narcolepsy opens up new perspectives. Narcolepsy is a complex disorder involving genetic, immune and environmental factors. Although only a strong association is found with the HLA DQB1*0602 gene, other genetic susceptibility factors might be involved. Among these, the functional polymorphism of the catechol-O-methyltransferase (COMT) gene is critically involved in the severity of narcolepsy and in the response to the stimulant modafinil. Other pharmacogenetic targets include the orexinergic, noradrenergic and possibly the serotonergic pathways.