With an antiserum against substance P a small number of neurons could be resolved in great detail in the nervous system of the fruitfly Drosophila melanogaster. In the brain, 10 substance P-like immunoreactive (SPLI) neurons were individually identified. Two of these form extensive bilateral connections with dorsal and ventral protocerebral neuropil. Another two neurons have cell bodies located ventrally in the subesophageal ganglion and processes throughout subesophageal neuropil. In the thoracico-abdominal ganglia 10 SPLI neurons could be identified. Eight of these have large cell bodies located ventrally in thoracic ganglia and two have small cell bodies located posteriorly in the abdominal ganglia. Six of the 8 thoracic SPLI neurons could be resolved in detail and were found to form: (1) processes in dorsal thoracic and abdominal neuropil as well as processes running through the cervical connective into the subesophageal ganglia; and (2) processes running into the dorsal neural sheath of the thoracic ganglia. The latter processes form an extensive network of varicose terminals over the thoracic ganglia. Our results indicate that a substance P-like neuropeptide can act as a neurohormone released into the circulation from terminals in the neural sheath as well as a neurotransmitter/neuromodulator released by interneurons in the brain.