The melanocortin-2 receptor accessory protein-2 (MRAP2) is a single transmembrane protein that interacts with metabolic G protein-coupled receptors (GPCRs) including the melanocortin receptor 4 (MC4R) and the ghrelin receptor (GHSR) to potentiate their signalling. Human mutations in MRAP2 cause obesity, with hyperglycaemia and hypertension. However, functional studies that have only measured the effect of MRAP2 variants on MC4R-mediated cAMP signaling have produced inconsistent findings and most do not reduce MC4R function. Moreover, there are unanswered questions regarding how MRAP2 forms heterodimers with GPCRs, the structural regions involved in facilitating GPCR signalling and how human mutations in MRAP2 affect receptor signalling and trafficking. Here we used single-molecule microscopy and a range of signalling assays to demonstrate that: i) MRAP2 variants which have been identified in overweight or obese individuals impair MC4R function by multiple signalling pathways; ii) that MRAP2 directly interacts with the melanocortin receptor 3 (MC3R) that regulates timing of sexual maturation, rate of linear growth and lean mass accumulation; and iii) MRAP2 has unique structural regions that help facilitate GPCR signalling. I will discuss how these studies have revealed new insights into the molecular mechanisms by which MRAP2 regulates GPCR function and how these pathways are disrupted by obesity-associated MRAP2 genetic variants.