The acquisition of a hypothalamic-pituitary axis was a seminal event in vertebrate evolution leading to the neuroendocrine control of many complex functions including growth, reproduction, osmoregulation, stress and metabolism. Lampreys as basal vertebrates are the earliest evolved vertebrates for which there are demonstrated functional roles for two gonadotropin-releasing hormones (GnRHs) that act via the hypothalamic-pituitary-gonadal axis controlling reproductive processes. With the availability of the lamprey genome, we have identified a novel GnRH form (lamprey GnRH-II) and a novel glycoprotein hormone receptor, lGpH-R II (thyroid-stimulating hormone-like receptor). Based on functional studies, in situ hybridization and phylogenetic analysis, we hypothesize that the newly identified lamprey GnRH-II is an ancestral GnRH to the vertebrate GnRHs. This finding opens a new understanding of the GnRH family and can help to delineate the evolution of the complex neuro/endocrine axis of reproduction. A second glycoprotein hormone receptor (lGpH-R II) was also identified in the sea lamprey. The existing data suggest the existence of a primitive, overlapping yet functional HPG and HPT endocrine systems in this organism, involving one possibly two pituitary glycoprotein hormones and two glycoprotein hormone receptors as opposed to three or four glycoprotein hormones interacting specifically with three receptors in gnathostomes. We hypothesize that the glycoprotein hormone/glycoprotein hormone receptor systems emerged as a link between the neuro-hormonal and peripheral control levels during the early stages of gnathostome divergence. The significance of the results obtained by analysis of the HPG/T axes in sea lamprey may transcend the limited scope of the corresponding physiological compartments by providing important clues in respect to the interplay between genome-wide events (duplications), coding sequence (mutation) and expression control level evolutionary mechanisms in definition of the chemical control pathways in vertebrates.