Nearly four decades of research have yielded thousands of publications on the physiology, pharmacology and therapeutic effects of TRH and TRH mimetic analogs. This work addresses both the neuroendocrine and the extrahypothalamic actions and functions of the tripeptide. The many reports of clinical effects of TRH in diverse medical conditions, unrelated to pituitary or thyroid function, can appear bewildering, as can its widespread involvement in a plethora of neuronal and physiological processes. Herein, we hypothesize that a logical and causal interrelationship exists between the fundamental molecular and cellular actions of TRH, its broader physiological functions and the therapeutic effects that attend the administration of exogenous TRH and TRH analogs. When viewed from this perspective, the basic neurobiological actions and functions of TRH provide a rational basis for understanding its diverse therapeutic effects. We posit: that the fundamental excitatory actions of TRH throughout the neuroaxis result from blocking various K+ channels linked to G-protein coupled TRH receptors in neurons and pituitary cells in distinct TRH-innervated anatomical pathways; that the functional consequences of blockade of these K+ channels are to enhance neuronal and secretory outputs in TRH regulatory circuits to modulate behavioral and energy homeostasis, and; that in clinical situations the resultant broad and useful therapeutic effects following administration of TRH reflect the state-dependent normalizing effects of activation of these regulatory circuits. In this light, the spectrum of reported clinical effects of TRH agonism remains unique and impressive but is less enigmatic. With the understanding that the neurobiological actions of TRH underlie and are rationally antecedent to its documented, extensive clinical 'normotrophic' effects, continued empirical efforts to assess the medical uses of TRH and related drugs seem rational and warranted. We predict that the range of disorders whose symptoms are alleviated by TRH therapy will continue to expand and that TRH agonism could conceivably become a near-universal therapeutic adjunct, particularly in the practice of neuropsychiatric medicine.