Modulation of the number of functional growth factor receptors on the epithelial cell surface that is exposed to the action of cognate ligands represents a key strategy in cellular physiology to regulate the proliferation rate and the differentiation process. The keratinocyte growth factor receptor (KGFR) and the epidermal growth factor receptor (EGFR), among the growth factor receptors expressed on keratinocytes, are believed to play a unique crucial role in controlling epithelial proliferation. KGFR and EGFR appear to also contribute to the cell differentiation process. Modulation of KGFR and EGFR on the proliferation rate and differentiation process has been reported either in in vivo or in vitro conditions. This article reviews the architecture, the ligand binding activated-signaling pathways, and the biologic effects of KGFR and EGFR on keratinocytes.