Chemotherapeutic　agents　induce　complex　tissue　responses　in　vivo　and　damage　normal　organ　functions.　Here　we　use　the　feather　follicle　to　investigate　details　of　this　damage　response.　We　show　that　cyclophosphamide　treatment,　which　causes　chemotherapy-induced　alopecia　in　mice　and　man,　induces　distinct　defects　in　feather　formation:　feather　branching　is　transiently　and　reversibly　disrupted,　thus　leaving　a　morphological　record　of　the　impact　of　chemotherapeutic　agents,　whereas　the　rachis　(feather　axis)　remains　unperturbed.　Similar　defects　are　observed　in　feathers　treated　with　5-fluorouracil　or　taxol　but　not　with　doxorubicin　or　arabinofuranosyl　cytidine　(Ara-C).　Selective　blockade　of　cell　proliferation　was　seen　in　the　feather　branching　area,　along　with　a　downregulation　of　sonic　hedgehog　(Shh)　transcription,　but　not　in　the　equally　proliferative　rachis.　Local　delivery　of　the　Shh　inhibitor,　cyclopamine,　or　Shh　silencing　both　recapitulated　this　effect.　In　mouse　hair　follicles,　those　chemotherapeutic　agents　that　disrupted　feather　formation　also　downregulated　Shh　gene　expression　and　induced　hair　loss,　whereas　doxorubicin　or　Ara-C　did　not.　Our　results　reveal　a　mechanism　through　which　chemotherapeutic　agents　damage　rapidly　proliferating　epithelial　tissue,　namely　via　the　cell　population　specific,　Shh-dependent　inhibition　of　proliferation.　This　mechanism　may　be　targeted　by　future　strategies　to　manage　chemotherapy-induced　tissue　damage.