This review of our literature describes the effects of many neuroleptic drugs on the sympathetic and hyperthermic reactions due to orexin A, a neuropeptide affecting body temperature and food intake by an increase in sympathetic activity. Haloperidol reduces, while clozapine and olanzapine block the hyperthermia induced by orexin A. Risperidone enhances the elevation of body temperature due to orexin A. Quetiapine delays these hyperthermic effects. The implications on human therapeutic strategies are discussed, including the involvement of orexinergic pathway in the induction of obesity, induced by these neuroleptic substances. We summarize our published data in a unique report so to emphasize the influences of these neuroleptic drugs on the control of body temperature, exerted by orexinergic system. This large vision could be also useful to address therapeutic choices.Patients with serious mental illness are at higher risk of developing metabolic abnormalities (e.g., weight gain, increased blood pressure, and glucose or lipid levels) in comparison to general population. Since the risk increases following initiation of narcoleptic therapy, it must assess carefully risks and benefits when choosing a particular antipsychotic drug.