The corticotropin-releasing hormone (CRH) system constitutes an evolutionarily ancient and conserved peptidergic network, the origins of which can be traced back to early bilaterian evolution, before the divergence of protostomes and deuterostomes. The extant CRH system-related ligands, cognate receptors and the binding protein descend from ancestral genes that were subjected to lineage-specific gene duplication or deletion events during evolution. In vertebrates, the present diversity of ligands and receptors is a result of two (2R) or even three (3R) rounds of whole-genome duplication (WGD). The early appearance of the CRH system during evolution and its conservation suggest its original involvement in fundamental processes that are essential for survival, including the maintenance of metabolic and physiological homoeostasis. CRH in vertebrates is well known as a secretagogue controlling the hypothalamic-pituitary-adrenal/interrenal (HPA/I) axis. The diuretic hormone 44 (DH44), which is the CRH homolog in arthropods, exerts control over multiple physiological processes ranging from nutrient sensing to reproductive behaviour. The bandwidth of functions assigned to this neuropeptide reflects different modes of organization that have adopted the CRH system as a central component of the neuroendocrine stress response system, integrating sensory information to convey physiological responses to external and internal alterations. In most vertebrates, CRH is not only regulating the HPA/I axis but simultaneously exercises control over the hypothalamic-pituitary-thyroid (HPT) axis. The observation that this function is lost in mammals and is restricted to the control of the HPA/I axis exemplifies how this system has been subjected to a constant process of adaptation during evolution. In this respect, the investigation of the CRH system in various taxa of animal evolution beyond humans and rodents has the potential to provide novel insights into our comprehension of this central neuroendocrine stress response system.