The orexin/hypocretin neuropeptide system plays a crucial role in various physiological and behavioral processes, serving as a powerful neuromodulator that shapes autonomic, endocrine, and behavioral responses across species. This review provides an overview of the evolution of our understanding of the orexin system, from its initial discovery to the promising progress in developing orexin derivatives. The authors have contributed significantly to the literature in fields such as stress response, fear, anxiety, and learning. The orexin system is particularly important in regulating vigilance and stress responses, and its roles in food intake, metabolism, and thermoregulation are complementary and warrant further investigation. The review also discusses the advancement of orexin pharmacology, highlighting its potential in treating sleep disorders. The orexin system's complex network in the CNS involves interactions with other neuropeptides, and its dysfunctions can lead to severe pathophysiological changes, including narcolepsy, obesity, and various neurological disorders. The review concludes by discussing the therapeutic potential of orexin receptor ligands in addressing these conditions.The orexin/hypocretin neuropeptide system plays a crucial role in various physiological and behavioral processes, serving as a powerful neuromodulator that shapes autonomic, endocrine, and behavioral responses across species. This review provides an overview of the evolution of our understanding of the orexin system, from its initial discovery to the promising progress in developing orexin derivatives. The authors have contributed significantly to the literature in fields such as stress response, fear, anxiety, and learning. The orexin system is particularly important in regulating vigilance and stress responses, and its roles in food intake, metabolism, and thermoregulation are complementary and warrant further investigation. The review also discusses the advancement of orexin pharmacology, highlighting its potential in treating sleep disorders. The orexin system's complex network in the CNS involves interactions with other neuropeptides, and its dysfunctions can lead to severe pathophysiological changes, including narcolepsy, obesity, and various neurological disorders. The review concludes by discussing the therapeutic potential of orexin receptor ligands in addressing these conditions.