As summarized with prescient insight by Berta Scharrer, classical neurosecretory neurons “differ from more conventional neural elements by specializing in the manufacture of chemical mediators to a degree comparable to that of gland cells and by engaging in modes of information transfer that markedly digress from standard synaptic transmission.” Their products are peptides, and she noted that these cells “seem to reach back to the very beginnings of the evolvement of a neural apparatus, when all of the endocrine functions had to be carried out by pluripotential neurons…. Gene duplication and enzymatic cleavage can be presumed to have been involved in the development, from an ancestral universal precursor, of peptidic entities with increasingly diversified functional properties” (Scharrer, Gen Comp Endocrinol 34:50–62, 1978). In all metazoans, multifunctional neurosecretory neurons release peptides that can act as both endocrine signals (neurohormones) and as locally acting paracrine/autocrine signals to other neurons. In lower invertebrates, such as annelids, at least half of the neurons in the cerebral ganglion are capable of both hormonal and local signaling. In this chapter, I discuss aspects of the evolution of the mammalian hypothalamo-neurohypophysial neurons from their invertebrate origins.