Melatonin, the hormone of darkness, is secreted in minute amounts during the night and is virtually undetectable during the day. Melatonin mainly acts on high-affinity G protein-coupled receptors. The present review will trace the path of the discovery of melatonin receptors from their cloning, expression and purification to the development of recent radioactive and fluorescent tracers. We will then report on the state-of-the-art of melatonin receptor functional properties, including ligand bias and system bias due to receptor-associated proteins and receptor heteromers. Currently available antibodies raised against melatonin receptors will be critically reviewed here for the first time. The review will close with future perspectives in terms of the discovery of allosteric ligands and the in vivo validation of a range of melatonin receptor-associated signaling complexes to improve future drug development.