The histaminergic neurons of the tuberomammillary nucleus (TMN^HDC) of the posterior hypothalamus have long been implicated in promoting arousal. More recently, a role for GABAergic signaling by the TMN^HDCneurons in arousal control has been proposed. Here, we investigated the effects of selective chronic disruption of GABA synthesis (via genetic deletion of the GABA synthesis enzyme, glutamic acid decarboxylase 67) or GABAergic transmission (via genetic deletion of the vesicular GABA transporter (VGAT)) in the TMN^HDCneurons on sleep–wake in male mice. We also examined the effects of acute chemogenetic activation and optogenetic inhibition of TMN^HDCneurons upon arousal in male mice. Unexpectedly, we found that neither disruption of GABA synthesis nor GABAergic transmission altered hourly sleep–wake quantities, perhaps because very few TMN^HDCneurons coexpressed VGAT. Acute chemogenetic activation of TMN^HDCneurons did not increase arousal levels above baseline but did enhance vigilance when the mice were exposed to a behavioral cage change challenge. Similarly, acute optogenetic inhibition had little effect upon baseline levels of arousal. In conclusion, we could not identify a role for GABA release by TMN^HDCneurons in arousal control. Further, if TMN^HDCneurons do release GABA, the mechanism by which they do so remains unclear. Our findings support the view that TMN^HDCneurons may be important for enhancing arousal under certain conditions, such as exposure to a novel environment, but play only a minor role in behavioral and EEG arousal under baseline conditions.SIGNIFICANCE STATEMENTThe histaminergic neurons of the tuberomammillary nucleus of the hypothalamus (TMN^HDC) have long been thought to promote arousal. Additionally, TMN^HDCneurons may counter-regulate the wake-promoting effects of histamine through co-release of the inhibitory neurotransmitter, GABA. Here, we show that impairing GABA signaling from TMN^HDCneurons does not impact sleep–wake amounts and that few TMN^HDCneurons contain the vesicular GABA transporter, which is presumably required to release GABA. We further show that acute activation or inhibition of TMN^HDCneurons has limited effects upon baseline arousal levels and that activation enhances vigilance during a behavioral challenge. Counter to general belief, our findings support the view that TMN^HDCneurons are neither necessary nor sufficient for the initiation and maintenance of arousal under baseline conditions.