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Melatonergic signalling is mediated by its two GPCRs, MT<jats:sub>1<\/jats:sub> and MT<jats:sub>2<\/jats:sub>, which are widely expressed in the mammalian CNS. Melatonin levels and receptor expression often show a decrease during normal ageing, and this reduction may be accelerated in some disease states. Depleted melatonergic signalling has been associated with neuropsychiatric dysfunction and impairments in cognition, memory, neurogenesis and neurorestorative processes. The anticonvulsant and mood stabilizer, valproic acid (VPA), up\u2010regulates melatonin MT<jats:sub>1<\/jats:sub> and\/or MT<jats:sub>2<\/jats:sub> receptor expression in cultured cells and in the rat brain. VPA is known to affect gene expression through several mechanisms, including the modulation of intracellular kinase pathways and transcription factors, as well as the inhibition of histone deacetylase (HDAC) activity. Interestingly, other HDAC inhibitors, such as trichostatin A, which are structurally distinct from VPA, can also up\u2010regulate melatonin receptor expression, unlike a VPA analogue, valpromide, which lacks HDAC inhibitory activity. Moreover, VPA increases histone H3 acetylation along the length of the MT<jats:sub>1<\/jats:sub> gene promoter in rat C6 cells. These findings indicate that an epigenetic mechanism, linked to histone hyperacetylation\/chromatin remodelling and associated changes in gene transcription, is involved in the up\u2010regulation of melatonin receptors by VPA. Epigenetic induction of MT<jats:sub>1<\/jats:sub> and\/or MT<jats:sub>2<\/jats:sub> receptor expression, in areas where these receptors are lost because of ageing, injury or disease, may be a promising therapeutic avenue for the management of CNS dysfunction and other disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. 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