Secretion of the pituitary glycoprotein hormones (GpH) follitropin, lutropin, and thyrotropin in vertebrates is the main mechanism by which neuroendocrine signals are propagated at the level of the peripheral glands, gonads and thyroid. Receptors of these hormones (glycoprotein hormone receptors, GpH-R) evolved from a common ancestor through gene duplication and subsequent functional divergence during the split of gnathostomes from their agnathan ancestors. Here we review the properties of two novel receptors closely related to gnathostome GpH-Rs identified in the sea lamprey. Although these are the oldest members of this family of receptors described so far in vertebrates, their overall structural features are remarkably close to their mammalian counterparts. However, they cannot be classified unequivocally as either gonadotropin (FSH-R, LH-R) or as thyrotropin receptors (TSH-R) since they share characteristics with both these groups. This may indicate that lamprey receptors reflect in part properties of the ancestral molecule(s) from which all vertebrate GpH-Rs originated. Molecular phylogenetic relationships among gnathostome GpH-Rs are heavily dependent on the functional domain used in analysis. This suggests large variation in functional constraints acting at the level of different segments of the receptor molecule.