Modafinil is a wake-promoting compound with low abuse potential used in the treatment of narcolepsy. Although the compound is reported to affect multiple neurotransmitter systems such as catecholamines, serotonin, glutamate, GABA, orexin, and histamine, however, the molecular mechanism by which modafinil increases wakefulness is debated. Herein we used dopamine (DA) D(2) receptor (D(2)R)-deficient mice combined with D(1)R- and D(2)R-specific antagonists to clarify the role of DA receptors in the arousal effects of modafinil. In wild-type mice, intraperitoneal modafinil induced wakefulness in a dose-dependent manner. Pretreatment with either D(1)R antagonist SCH23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] at 30 microg/kg or D(2)R antagonist raclopride at 2 mg/kg blocked the arousal effects of low-dose modafinil at 22.5 and 45 mg/kg. When modafinil was given at 90 and 180 mg/kg, pretreatment of D(1)R antagonist did not affect the wakefulness at all, whereas D(2)R antagonist significantly attenuated the wakefulness to the half level compared with vehicle control. Similarly, D(2)R knock-out (KO) mice exhibited attenuated modafinil-induced wakefulness. However, pretreatment of D(2)R KO mice with D(1)R antagonist completely abolished arousal effects of modafinil. These findings strongly indicate that dopaminergic D(1)R and D(2)R are essential for the wakefulness induced by modafinil.