This review briefly summarizes 50 years of research on insect neuropeptide and peptide hormone (collectively abbreviated NPH) signaling, starting with the sequencing of proctolin in 1975. The first 25 years, before the sequencing of the Drosophila genome, were characterized by efforts to identify novel NPHs by biochemical means, mapping of their distribution in neurons, neurosecretory cells, and endocrine cells of the intestine. Functional studies of NPHs were predominantly dealing with hormonal aspects of peptides and many employed ex vivo assays. With the annotation of the Drosophila genome, and more specifically of the NPHs and their receptors in Drosophila and other insects, a new era followed. This started with matching of NPH ligands to orphan receptors, and studies to localize NPHs with improved detection methods. Important advances were made with introduction of a rich repertoire of innovative molecular genetic approaches to localize and interfere with expression or function of NPHs and their receptors. These methods enabled cell- or circuit-specific interference with NPH signaling for in vivo assays to determine roles in behavior and physiology, imaging of neuronal activity, and analysis of connectivity in peptidergic circuits. Recent years have seen a dramatic increase in reports on the multiple functions of NPHs in development, physiology and behavior. Importantly, we can now appreciate the pleiotropic functions of NPHs, as well as the functional peptidergic “networks” where state dependent NPH signaling ensures behavioral plasticity and systemic homeostasis.