Neuropeptidases play a key role in regulating neuropeptide signalling activity in the central nervous system of animals. They are oligopeptidases that are generally found on the surface of neuronal cells facing the synaptic and peri-synaptic space and therefore are ideally placed for the metabolic inactivation of neuropeptide transmitters/modulators. This review discusses the structure of insect neuropeptides in relation to their susceptibility to hydrolysis by peptidases and the need for specialist enzymes to degrade many neuropeptides. It focuses on five neuropeptidase families (neprilysin, dipeptidyl-peptidase IV, angiotensin-converting enzyme, aminopeptidase and dipeptidyl aminopeptidase III) that have been implicated in the metabolic inactivation of neuropeptides in the central nervous system of insects. Experimental evidence for the involvement of these peptidases in neuropeptide metabolism is reviewed and their properties are compared to similar neuropeptide inactivating peptidases of the mammalian brain. We also discuss how the sequencing of insect genomes has led to the molecular identification of candidate neuropeptidase genes. (C) 2008 Elsevier Inc. All rights reserved.