The human MT and MT melatonin receptors are G-protein-coupled receptors (GPCRs) that help to regulate circadian rhythm and sleep patterns. Drug development efforts have targeted both receptors for the treatment of insomnia, circadian rhythm and mood disorders, and cancer, and MT has also been implicated in type 2 diabetes. Here we report X-ray free electron laser (XFEL) structures of the human MT receptor in complex with the agonists 2-phenylmelatonin (2-PMT) and ramelteon at resolutions of 2.8 Å and 3.3 Å, respectively, along with two structures of function-related mutants: H208A (superscripts represent the Ballesteros-Weinstein residue numbering nomenclature) and N86D, obtained in complex with 2-PMT. Comparison of the structures of MT with a published structure of MT reveals that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in [H]melatonin dissociation kinetics that provide insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel is observed in both MT and MT, but in addition the MT structures reveal a narrow opening towards the solvent in the extracellular part of the receptor. We provide functional and kinetic data that support a prominent role for intramembrane ligand entry in both receptors, and suggest that there might also be an extracellular entry path in MT. Our findings contribute to a molecular understanding of melatonin receptor subtype selectivity and ligand access modes, which are essential for the design of highly selective melatonin tool compounds and therapeutic agents.