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Transduction of mechanical stimuli by receptor cells is essential for senses such as hearing, touch and pain1,2,3,4. Ion channels have a role in neuronal mechanotransduction in invertebrates1; however, functional conservation of these ion channels in mammalian mechanotransduction is not observed. For example, no mechanoreceptor potential C (NOMPC), a member of transient receptor potential (TRP) ion channel family, acts as a mechanotransducer inDrosophila melanogaster5andCaenorhabditis elegans6,7; however, it has no orthologues in mammals. Degenerin/epithelial sodium channel (DEG/ENaC) family members are mechanotransducers inC. elegans8and potentially inD. melanogaster9; however, a direct role of its mammalian homologues in sensing mechanical force has not been shown. Recently, Piezo1 (also known as Fam38a) and Piezo2 (also known as Fam38b) were identified as components of mechanically activated channels in mammals10. The Piezo family are evolutionarily conserved transmembrane proteins. It is unknown whether they function in mechanical sensingin vivoand, if they do, which mechanosensory modalities they mediate. Here we study the physiological role of the single Piezo member inD. melanogaster(Dmpiezo; also known as CG8486). Dmpiezoexpression in human cells induces mechanically activated currents, similar to its mammalian counterparts11. Behavioural responses to noxious mechanical stimuli were severely reduced in Dmpiezoknockout larvae, whereas responses to another noxious stimulus or touch were not affected. Knocking down Dmpiezoin sensory neurons that mediate nociception and express the DEG/ENaC ion channelpickpocket(ppk) was sufficient to impair responses to noxious mechanical stimuli. Furthermore, expression of Dmpiezoin these same neurons rescued the phenotype of the constitutive Dmpiezoknockout larvae. Accordingly, electrophysiological recordings fromppk-positive neurons revealed a Dmpiezo-dependent, mechanically activated current. Finally, we found that Dmpiezoandppkfunction in parallel pathways inppk-positive cells, and that mechanical nociception is abolished in the absence of both channels. These data demonstrate the physiological relevance of the Piezo family in mechanotransductionin vivo, supporting a role of Piezo proteins in mechanosensory nociception.