We investigated the interaction between norepinephrine (NE) and orexin/hypocretin (Hcrt) in the control of sleep behavior and narcoleptic symptoms by creating mice that were deficient in both neurotransmitters. Mice with a targeted disruption of the dopamine β-hydroxylase (Dbh) gene (deficient in NE and epinephrine) or the Hcrt gene were bred to generate double knockouts (DKOs), each single KO (Dbh-KO and Hcrt-KO), and control mice. The duration of wake, non-rapid eye movement (NREM) and REM sleep were monitored by electroencephalogram (EEG)/electromyogram (EMG) recording over a 24-h period, and the occurrence of behavioral arrests was monitored by video/EEG recording for 4 h. Overall, there was very little interaction between the two genes; for most parameters that were measured, the DKO mice resembled either Dbh-KO or Hcrt-KO mice. REM sleep was increased in both DKO and Hcrt-KO mice at night relative to the other groups, but DKO mice had significantly more REM sleep during the day than the other three groups. Sleep latency in response to saline or amphetamine injections was reduced in Dbh-KO and DKO mice relative to other groups. Behavioral arrests, that are frequent in Hcrt-KO mice, were not exacerbated in DKO mice.