Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation. Transition of epithelial/mesothelial cells into myofibroblasts [epithelial‐to‐mesenchymal transition (EMT)] occurs under the influence of transforming growth factor (TGF)‐β1, with Snail being a major transcription factor. We study here the role of the heat‐shock protein HSP27 in fibrogenesis and EMT. In vitro, we have up‐ and down‐modulated HSP27 expression in mesothelial and epithelial cell lines and studied the expression of different EMT markers induced by TGF‐β1. In vivo, we inhibited HSP27 with the antisense oligonucleotide OGX‐427 (in phase II clinical trials as anticancer agent) in our rat subpleural/pulmonary fibrosis models. We demonstrate that HSP27 is strongly expressed during the fibrotic process in patients with IPF and in different in vivo models. We showed that HSP27 binds to and stabilizes Snail and consequently induces EMT. Conversely, HSP27 knockdown leads to Snail proteasomal degradation, thus inhibiting TGF‐β1‐induced EMT. Inhibition of HSP27 with OGX‐427 efficiently blocks EMT and fibrosis development. Controls in vivo were an empty adenovirus that did not induce fibrosis and a control antisense oligonucleotide. The present work opens the possibility of a new therapeutic use for HSP27 inhibitors against IPF, for which there is no conclusively effective treatment.—Wettstein, G., Bellaye, P.‐S., Kolb, M., Hammann, A., Crestani, B., Soler, P., Marchal‐Somme, J., Hazoume, A., Gauldie, J., Gunther, A., Micheau, O., Gleave, M., Camus, P., Garrido, C., Bonniaud, P. Inhibition of HSP27 blocks fibrosis development and EMT features by promoting Snail degradation. FASEB J. 27, 1549–1560 (2013). www.fasebj.org