The functions of thyrotropin-releasing hormone (TRH) in the central nervous system (CNS) can be conceptualized as performed by four anatomically distinct components that together comprise a general TRH homeostatic system. These components are 1) the hypothalamic-hypophysiotropic neuroendocrine system, 2) the brainstem/midbrain/spinal cord system, 3) the limbic/cortical system, and 4) the chronobiological system. We propose that the main neurobiological function of TRH is to promote homeostasis, accomplished through neuronal mechanisms resident in these four integrated systems. This hypothesis offers a unifying basis for understanding the myriad actions of TRH and TRH-related drugs already demonstrated in animals and humans. It is consistent with the traditional role of TRH as a regulator of metabolic homeostasis. An appreciation of the global function of TRH to modulate and normalize CNS activity, along with an appreciation of the inherent limitations of TRH itself as a therapeutic agent, leads to rational expectations of therapeutic benefit from metabolically stable TRH-mimetic drugs in a remarkably broad spectrum of clinical situations, both as monotherapy and as an adjunct to other therapeutic agents. The actions of TRH are numerous and varied. This has been viewed in the past as a conceptual and practical impediment to the development of TRH analogs. Herein, we alternatively propose that these manifold actions should be considered as a rational and positive impetus to the development of TRH-based drugs with the potential for unique and widespread applicability in human illness.