The growing number of recently identified negative feedback regulators of receptor tyrosine kinases (RTKs) highlights the importance of signal attenuation and modulation for correct signaling outcome. Mitogen-inducible gene 6 (Mig6 also known as RALT or Gene 33) is a multiadaptor protein thought to be involved in the regulation of RTK and stress signaling. Here, we show that deletion of the mouse gene encoding Mig6 (designated Errfi1, which stands for ERBB receptor feedback inhibitor 1) causes hyperactivation of endogenous epidermal growth factor receptor (EGFR) and sustained signaling through the mitogen-activated protein kinase (MAPK) pathway, resulting in overproliferation and impaired differentiation of epidermal keratinocytes. Furthermore, Errfi1-/- mice develop spontaneous tumors in various organs and are highly susceptible to chemically induced formation of skin tumors. A tumor-suppressive role for Mig6 is supported by our finding that MIG6 is downregulated in various human cancers. Inhibition of endogenous Egfr signaling with the Egfr inhibitor gefitinib (Iressa) or replacement of wild-type Egfr with the kinase-deficient protein encoded by the hypomorphic Egfr(wa2) allele completely rescued skin defects in Erffi1-/- mice. Carcinogen-induced tumors displayed by Errfi1-/- mice were highly sensitive to gefitinib. These results indicate that Mig6 is a specific negative regulator of Egfr signaling in skin morphogenesis and is a novel tumor suppressor of Egfr-dependent carcinogenesis.