The epidermal growth factor receptor (EGFR) network, including its seven ligands and four related receptors, represents one of the most complex signaling systems in biology. In many tissues, including the skin and its appendages (notoriously the hair follicles), its correct function is necessary for proper development and tissue homeostasis, and its deregulation rapidly results in defects in cellular proliferation and differentiation. The consequences are impaired wound healing, development of psoriasis-like lesions, structural and functional defects of the hair follicles, and tumorigenesis. In addition to in vitro experiments and data from clinical studies, several genetically modified mouse models displaying alterations in the interfollicular skin and hair follicles attributable to mutations in components of the EGFR system have been reported. These animals, in many cases representing bona fide models of known human diseases, have been seminal in the study of the role of EGFR and its ligands in the skin and its appendages. In this review, we take the multiple phenotypes of these animal models as a basis to summarize and discuss the effects elicited by members of the EGFR system in diverse aspects of skin biology and pathology, including cellular proliferation and differentiation, wound healing, hair follicle morphogenesis, and tumorigenesis. Copyright © American Society for Investigative Pathology.