Fibrosis is characterised by the irreversible accumulation and excessive remodelling of extracellular matrix (ECM), and is caused by the uncontrolled activation and secretion of transforming growth factor β (TGFβ) by myofibroblasts. Normal fibroblasts sequester latent TGF-β1 in the ECM in complex with TGF-β binding protein-1 (LTBP-1), which also interacts with fibronectin (FN). There are several splice variants of FN, and its ED-A isoform (ED-A FN) has been shown to be necessary for myofibroblast activation during fibrosis. In this study (Klingberg et al.), Boris Hinz and co-workers test the hypothesis of whether EDA-FN is involved in controlling the amount of latent TGF-β1 in the ECM. By using human dermal fibroblasts cultured on stiffness-tuneable substrates, they show that ECM stiffness, which induces myofibroblast activation, results in the upregulation of both ED-A FN and LTBP-1, and the enhanced incorporation of LTBP-1 into the ECM. Accordingly, function-blocking antibodies against ED-A FN resulted in a decrease in LTBP-1 incorporation into the ECM, and in reduced TGF-β1 activation. As ED-A FN is upregulated in fibrosis and is induced by TGF-β1, the interaction between LTBP-1 and ED-A FN may contribute to a feed-forward loop that results in the persistent activation of myofibroblasts and, subsequently, fibrosis. Therefore, these findings also raise the possibility of targeting ED-A FN as a potential anti-fibrotic strategy.