The epidermal growth factor receptor (EGFR) family of receptors and the transforming growth factor-β (TGF-β) family are active in diverse biological processes and are central mediators in the initiation and maintenance of fibrosis in many diseases. Transforming growth factor-α (TGFα) is a ligand for the EGFR, and doxycycline (Dox)-inducible transgenic mice conditionally expressing TGFα specifically in the lung epithelium develop progressive fibrosis. The αvβ6 integrin is an important in vivo activator of TGF-β activation in the lung. Immunohistochemical analysis of αvβ6 protein expression and bronchoalveolar analysis of TGFβ pathway signaling indicates activation of the αvβ6/TGFβ pathway only at later time points after lung fibrosis was already established in the TGFα model. To determine the contribution of the αvβ6/TGFβ pathway on the progression of established fibrotic disease, TGFα transgenic mice were administered Dox for 4 weeks which leads to extensive fibrosis; these mice were then treated with a function blocking anti-αvβ6 antibody with continued administration of Dox for an additional 4 weeks. Compared to TGFα transgenic mice treated with control antibody, αvβ6 inhibition significantly attenuated pleural thickening and altered the decline in lung mechanics. To test the effects of genetic loss of the β6 integrin, TGFα transgenic mice were mated with β6 null mice and the degree of fibrosis compared in adult mice following 8 weeks of Dox administration. Genetic ablation of the β6 integrin attenuated histologic and physiologic changes in the lungs of TGFα transgenic mice although a significant degree of fibrosis still developed.