AbstractThe 5 known melanocortin receptors (MCs) have established physiological roles. With the exception of MC2, these receptors can behave unpredictably, and since they are more widely expressed than their established roles would suggest, it is likely that they have other poorly characterized functions. The aim of this review is to discuss some of the less well-explored aspects of the 4 enigmatic members of this receptor family (MC1,3-5) and describe how these are multifaceted G protein–coupled receptors (GPCRs). These receptors appear to be promiscuous in that they bind several endogenous agonists (products of the proopiomelanocortin [POMC] gene) and antagonists but with inconsistent relative affinities and effects. We propose that this is a result of posttranslational modifications that determine receptor localization within nanodomains. Within each nanodomain there will be a variety of proteins, including ion channels, modifying proteins, and other GPCRs, that can interact with the MCs to alter the availability of receptor at the cell surface as well as the intracellular signaling resulting from receptor activation. Different combinations of interacting proteins and MCs may therefore give rise to the complex and inconsistent functional profiles reported for the MCs. For further progress in understanding this family, improved characterization of tissue-specific functions is required. Current evidence for interactions of these receptors with a range of partners, resulting in modulation of cell signaling, suggests that each should be studied within the full context of their interacting partners. The role of physiological status in determining this context also remains to be characterized.