The neuropeptides oxytocin (OT) and vasopressin (VP) are well-known for their peripheral hormonal effects, and act as key neuromodulators in the mammalian brain influencing social behavior and cognition. Homologous neuropeptides are widely distributed among the invertebrate lineage as well, suggesting an ancient origin for this neuropeptide family. Whereas hormonal effects of OT/VP-related signaling such as on reproduction and myoactivity seem to be well conserved, potential neuromodulatory effects remain largely unexplored in invertebrates, keeping their evolutionary origin in the dark.The nematode Caenorhabditis elegans has a small nervous system of only 302 neurons, but despite its small size harbors a wide plethora of over 250 bioactive peptides. Using a combined bio-informatic and reverse pharmacology approach, we have identified a signaling system related to OT and VP signaling in C. elegans. Similar to most invertebrates, C. elegans has a single OT/VP-related peptide – designated nematocin – that dose-dependently activates a G protein-coupled receptor (NTR-1). In vivo localization highlights a putative role of nematocin signaling in modulating the sensory neural circuit, and knockout of nematocin or its receptor in C. elegans caused defects in gustatory associative learning. We found that nematocin is released from specific interneurons activating its receptor on a gustatory neuron of the learning circuit, and interacts with serotonergic and dopaminergic neurotransmission. In addition, we have identified several other evolutionary conserved neuropeptide systems in C. elegans including tachykinin and neuromedin related signaling and are currently characterizing their modulatory role in behavioral plasticity.Our study suggests that neuropeptides of the oxytocin/vasopressin family are ancient modulators of neural circuits underlying behavioral plasticity, and sheds light on the cellular and molecular networks behind these effects.