Among epidermal growth factors, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is expressed unlike others, and produces unusual effects on keratinocytes. A new report illustrates the development of a motile phenotype characterized by signs of epithelial–mesenchymal transition, reduced proliferation, and altered expression of epidermal markers. We comment on differences between endogenous HB-EGF and recombinant factor, about opportune and inopportune situations of HB-EGF overexpression by epidermal keratinocytes, as well as about the consequences on epidermal tissues.