AbstractGhrelin receptors are expressed by key components of the arousal system. Exogenous ghrelin induces behavioral activation, promotes wakefulness and stimulates eating. We hypothesized that ghrelin‐sensitive mechanisms play a role in the arousal system. To test this, we investigated the responsiveness of ghrelin receptor knockout (KO) mice to two natural wake‐promoting stimuli. Additionally, we assessed the integrity of their homeostatic sleep‐promoting system using sleep deprivation. There was no significant difference in the spontaneous sleep–wake activity between ghrelin receptor KO and wild‐type (WT) mice. WT mice mounted robust arousal responses to a novel environment and food deprivation. Wakefulness increased for 6 h after cage change accompanied by increases in body temperature and locomotor activity. Ghrelin receptor KO mice completely lacked the wake and body temperature responses to new environment. When subjected to 48 h food deprivation, WT mice showed marked increases in their waking time during the dark periods of both days. Ghrelin receptor KO mice failed to mount an arousal response on the first night and wake increases were attenuated on the second day. The responsiveness to sleep deprivation did not differ between the two genotypes. These results indicate that the ghrelin‐receptive mechanisms play an essential role in the function of the arousal system but not in homeostatic sleep‐promoting mechanisms.