Thyrotropin-releasing hormone (TRH) is a crucial regulator of the hypothalamus-pituitary-thyroid-axis and metabolism in mammals. TRH is highly conserved since it is detected in the genome/nervous system of phylogenetic clades across protostomes to deuterostomes. However, variations in the amino acid (aa) sequence, neuroanatomical distribution, and functional properties are quite common. While the 5–8 aa TRH-like peptides have been identified in protostomes, 4 aa TRH with pyroglutamate residue appears first in deuterostomes like echinoderms. However, its tripeptide amide nature was encountered first in Branchiostoma and vertebrates. In vertebrates, TRH is abundantly expressed in the brains of mammals and nonmammals. The organization of TRH-containing elements in the brain of cyclostomes through mammals shows profound evolutionary changes. Distinct hypophysiotropic TRHergic system in the brain of mammals and birds may have evolved from the cerebrospinal-fluid-contacting TRH neurons in the preoptic area/hypothalamus of lower vertebrates. The nonhypophysiotropic TRH system seems engaged in regulating the hypophysiotropic dopamine neurons in teleosts and mammals. Dense TRHergic neuronal groups were found in the brains of teleosts and mammals, followed by other vertebrates. TRH functions as a multifunctional hypophysiotropic factor and serves as an essential regulator of metamorphosis as well as metabolism in vertebrates. The central inhibitory action of neuropeptide Y (NPY) on the hypophysiotropic TRH neurons in mammals is conserved in birds. However, the NPY-TRH response to changing energy states is more rapid in birds. Its ancient origin, neurotransmitter-like characteristics, wide neuroanatomical presence, and conserved features suggest TRH to be an essential central regulator.