The pharmacology and function of G protein-coupled receptors (GPCRs) is frequently studied following expression of a single receptor in heterologous cell lines. However, many GPCRs are co-expressed. We wished to investigate how expression of pairs of receptors might modulate their function. Using a Human Embryonic Kidney 293 cell line in which the CB1 cannabinoid receptor was expressed constitutively and in which varying levels of expression of the orexin-1 receptor could be induced by addition of doxycycline we demonstrated that in the presence of the CB1 receptor the orexin-1 receptor adopted a spontaneous, agonist-independent recycling phenotype that was indistinguishable from that of the CB1 receptor. By contrast, when expression of the orexin-1 receptor was induced in the absence of the CB1 receptor the orexin-1 receptor was plasma membrane delineated and required addition of the peptide orexin-A to induce internalisation. Using single cell fluorescence resonance energy transfer imaging, the co-expressed CB1 and orexin-1 receptors were shown to be present within an oligomeric complex. Although CB1 antagonists, including Rimonabant, have no inherent affinity for the orexin-1 receptor, treatment of cells co-expressing the CB1 and orexin-1 receptors resulted in redistribution of both the CB1 receptor and the orexin-1 receptor to the cell surface. Similarly, treatment of these cells with orexin-1 receptor antagonists with no affinity for the CB1 receptor caused both receptors to redistribute to the plasma membrane. These results introduce an novel pharmacological paradigm, due to hetero-oligomerisation, a GPCR can be regulated by receptor ligands that do not actually bind to the receptor in question. This can only occur in physiological cells and system in which relevant pairs of receptors are co-expressed. Such interactions may be relevant to the clinical effects of a number of medicines targeted at GPCRs.