Publisher Summary This chapter focuses on new functions of thyrotrophin-releasing hormone (TRH). TRH was the first of the hypothalamic releasing factors to be fully characterized. It consists of the tripeptide pGlu-His-Pro-NH2 that is derived from a precursor protein with multiple copies of the precursor sequence Lys-Arg-Gln-His-Pro-Gly-(Lys/Arg)-Arg. Pre-proTRH is distributed throughout the animal kingdom, occurring in species lacking a pituitary. In addition to its neuroendocrine release from the hypothalamus of mammals, resulting in secretion of TSH and PRL from the anterior pituitary, it functions as a neurotransmitter, neuromodulator, and neuroprotective agent in the central and peripheral nervous systems. Unlike hypothalamic preproTRH mRNA levels and TRH content that are subject to thyroid hormone negative feedback inhibition, extrahypothalamic brain TRH biosynthesis and release are unresponsive to thyroid hormone status. TRH is the principal regulator of the “set point” for thyrotrophin (TSH) synthesis and secretion by the anterior pituitary thyrotrophs. Moreover, TRH has an essential neuroprotective function that is mediated by its suppression of glycogen synthase kinase-3β (GSK-3β) expression in neurons. This enzyme is responsible for the hyperphosphorylation of tau that results in neurofibrillary tangles that are associated with the neuropathologies of Alzheimer's and other dementias and regulates microtubule assembly in nerve axons and dendrites.