Epidermal growth factor receptor (EGFR)–targeted anticancer therapy induces stigmatizing skin toxicities affecting patients’ quality of life and therapy adherence. The lack of mechanistic details underlying these adverse events hampers their management. We found that EGFR/ERK signaling is required in LRIG1-positive stem cells during de novo hair eruption to secure barrier integrity and prevent the invasion of commensal microbiota and inflammatory skin disease. Restoration of epidermal ERK signaling via prophylactic FGF7 treatment or transgenic SOS expression rescues the barrier defect in the absence of EGFR, highlighting a therapeutic anchor point. This study aims to improve the cancer patients´ quality of life and to optimize the efficacy of modern cancer treatment.