© The Author(s) 2016. Matrix stiffening is a prominent feature of pulmonary fibrosis. In this study, we demonstrate that matrix stiffness regulates the ability of fibrotic lung myofibroblasts to invade the basement membrane (BM). We identify α 6-integrin as a mechanosensing integrin subunit that mediates matrix stiffness-regulated myofibroblast invasion. Increasing α 6-expression, specifically the B isoform (α 6 B), couples β 1-integrin to mediate MMP-2-dependent pericellular proteolysis of BM collagen IV, leading to myofibroblast invasion. Human idiopathic pulmonary fibrosis lung myofibroblasts express high levels of α 6-integrin in vitro and in vivo. Genetic ablation of α 6 in collagen-expressing mesenchymal cells or pharmacological blockade of matrix stiffness-regulated α 6-expression protects mice against bleomycin injury-induced experimental lung fibrosis. These findings suggest that α 6-integrin is a matrix stiffness-regulated mechanosensitive molecule which confers an invasive fibroblast phenotype and mediates experimental lung fibrosis. Targeting this mechanosensing α 6 (β 1)-integrin offers a novel anti-fibrotic strategy against lung fibrosis.