Neuropeptides are peptide neuromodulators that are expressed by neurons and act on neural targets by activating neuropeptide receptors1. These receptors serve as therapeutic targets for the treatment of a number of pathophysiological conditions, including obesity, pain and addiction2-6. Major technological advances in the 1980s involving improved sensitivity of peptide purification methods and single neuron mRNA sequencing techniques have led to an explosion in the number of newly discovered neuropeptides7. However, to date, receptors for many of these neuropeptides remain largely unknown. In addition, currently there are a number of "orphan" G-protein-coupled receptors (GPCRs) for which endogenous ligands or function are yet to be identified8, 9.These "orphan" neuropeptides and GPCRs represent an untapped resource for the development of therapeutics to treat chronic diseases including drug abuse disorders, obesity and neuropathic pain. With this in mind much effort has been put towards deorphanizing these "orphan" peptides/GPCRs. Here, we summarize current insights into one such relationship: that between the neuropeptide PEN and the GPCR named GPR83. This intriguing system promises to deepen our current understanding of neuropeptide/GPCR systems, but also highlights the necessity for further technological advances in order to fully understand its complexity.