© 2018 Elsevier Ltd Oxytocin mediates its behavioural effects via the centrally expressed oxytocin receptor (OTR). Oxytocin signalling has been implicated in multiple disorders involving centrally regulated pathways, including obesity, autism, schizophrenia and depression. The OTR has been described to have a complex downstream signalling pathway and an increased understanding of oxytocinergic signalling is needed for the development of novel and better treatments for centrally regulated disorders. The ghrelin receptor (GHSR), known primarily for its role in centrally regulated energy balance and food intake, has in more recent years also been shown to play a role in mood disorders, including anxiety and depression. Although there have been suggestions of crosstalk between both signalling systems, these have largely been unexplored to date. Here we show, to our knowledge for the first-time, compelling evidence for the formation of an OTR and GHSR heterocomplex, resulting in significant modulation of OTR downstream signalling. Co-localized expression of the OTR and GHSR is shown in a heterologous cellular expression system and in primary cultures of the hypothalamus and hippocampus. A physical interaction between the OTR and GHSR is confirmed using flow-cytometry based fluorescence resonance energy transfer (fcFRET). Interestingly, co-expression of the GHSR results in a significant attenuation of OTR-mediated Gaq signalling and changes in receptor trafficking within the cell. Together, these data demonstrate a potential functional relevance of an OTR/GHSR heterocomplex and its ability to alter OTR signalling, which is poised to have important implications for future therapeutic strategies, involving oxytocinergic signalling. This article is part of the Special Issue entitled ‘Receptor heteromers and their allosteric receptor-receptor interactions’.