One‐third of the ∼400 nonodorant G protein‐coupled receptors (GPCRs) are still orphans. Although a considerable number of these receptors are likely to transduce cellular signals in response to ligands that remain to be identified, they may also have ligand‐independent functions. Several members of the GPCR family have been shown to modulate the function of other receptors through heterodimerization. We show that GPR50, an orphan GPCR, heterodimerizes constitutively and specifically with MT1 and MT2 melatonin receptors, using biochemical and biophysical approaches in intact cells. Whereas the association between GPR50 and MT2 did not modify MT2 function, GPR50 abolished high‐affinity agonist binding and G protein coupling to the MT1 protomer engaged in the heterodimer. Deletion of the large C‐terminal tail of GPR50 suppressed the inhibitory effect of GPR50 on MT1 without affecting heterodimerization, indicating that this domain regulates the interaction of regulatory proteins to MT1. Pairing orphan GPCRs to potential heterodimerization partners might be of clinical importance and may become a general strategy to better understand the function of orphan GPCRs.