Eph receptors and ephrin ligands are widely expressed during embryonic development with well-defined functions in directing neuronal and vascular network formation. Over the last decade, evidence has mounted that Ephs and ephrins are also actively involved in prenatal and postnatal development of epithelial tissues. Their functions beyond developmental settings are starting to be recognized as well. The diverse functions of Eph/ephrin are largely related to the complementary expression pattern of the Eph receptors and corresponding ephrin ligands that are expressed in adjacent compartments, although overlapping expression pattern also exists in epithelial tissue. The interconnection between Ephs or ephrins and classical cell junctional molecules suggests they may function coordinately in maintaining epithelial structural integrity and homeostasis. This review will highlight cellular and molecular evidence in current literature that support a role of Eph/ephrin systems in regulating epithelial cell development and physiology.