The control of cell growth is regulated through coordinated responses to growth factors and cell-extracellular matrix (ECM) interactions. Integrins, the major family of cell-ECM receptors, are vital to these coordinated responses. Although much is known of the role of integrins in growth promotion, specific examples of integrin-mediated cell growth inhibition are few. On the basis of our findings that the integrin β8 subunit is expressed in airway epithelial cells and is absent in lung cancers, we investigated the role and mechanism of the integrinαvβ8 in mediating growth inhibition. When introduced into either a lung or colon carcinoma cell line, β8 inhibited cell growth without inducing apoptosis. Ligation of αvβ8 also induced cell rounding,inhibited focal contact formation, and initiated an inhibitory signaling pathway as demonstrated by increased expression of the cyclin-dependent kinase inhibitor p21^Cip1. The cytoplasmic domain of β8 was capable of both growth inhibition and causing cell shape changes as shown by the use of a chimeric integrin construct consisting of the β8-cytoplasmic domain coupled to theβ6-extracellular domain. Finally, when tested in vivo,β8 potently inhibited tumor growth in nude mice. Together, these results implicate αvβ8 as a novel growth-regulatory molecule of epithelial cells.