The wealth of expression and functional data presented in this overview discloses the homeogene Orthopedia (Otp) as critical for the development of the hypothalamic neuroendocrine system of vertebrates. Specifically, the results depict the up-to-date portrait of the regulation and functions of Otp. The development of neuroendocrine nuclei relies on Otp from fish to mammals, as demonstrated for several peptide and hormone releasing neurons. Additionally, the activity of Otp is essential for the induction of the dopaminergic phenotype in the hypothalamus of vertebrates. Recent insights into the pathways required for Otp regulation have revealed the implication of the main extracellular signals acting during hypothalamic development. Alterations in these pathways are involved in several neuronal disorders, and the resultant downstream misregulation of Otp might impair the development of the hypothalamus, and be therefore responsible for the neuroendocrine dysfunctions that typify these diseases. Developmental Dynamics 237:2295–2303, 2008. © 2008 Wiley-Liss, Inc.