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Activation of orexin receptors promotes waking and is essential for expression of normal sleep and waking behaviour, with the sleep disorder narcolepsy resulting from the absence of orexin signalling. Orexin receptors also influence systems regulating appetite\/metabolism, stress and reward, and are found in several peripheral tissues. Nevertheless, much remains unknown about the signalling pathways and targets engaged by native receptors. In this review, we integrate knowledge about the orexin receptor signalling capabilities obtained from studies in expression systems and various native cell types (as presented in <jats:styled-content style=\"fixed-case\">K<\/jats:styled-content>ukkonen and <jats:styled-content style=\"fixed-case\">L<\/jats:styled-content>eonard, this issue of <jats:italic>British Journal of Pharmacology<\/jats:italic>) with knowledge of orexin signalling in different tissues. The tissues reviewed include the <jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content>, the gastrointestinal tract, the pituitary gland, pancreas, adrenal gland, adipose tissue and the male reproductive system. We also summarize the findings in different native and recombinant cell lines, especially focusing on the different cascades in <jats:styled-content style=\"fixed-case\">CHO<\/jats:styled-content> cells, which is the most investigated cell line. This reveals that while a substantial gap exists between what is known about orexin receptor signalling and effectors in recombinant systems and native systems, mounting evidence suggests that orexin receptor signalling is more diverse than originally thought. Moreover, rather than being restricted to orexin receptor \u2018overexpressing\u2019 cells, this signalling diversity may be utilized by native receptors in a site\u2010specific manner.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>This article is part of a themed section on Orexin Receptors. 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