Abbreviations: ADAM, a disintegrin and metalloprotease; Apc, adenomatous polyposis coli; Eph, erythropoietin-producing hepatocellular; ER, estrogen receptor; Erk, extracellular signal-regulated kinase; GEF, guanine nucleotide exchange factor; GPI, glycosylphosphatidylinositol; HER2, human epidermal growth factor receptor 2; HGF, hepatocyte growth factor; IBD, inflammatory bowel disease; KLF, Kr€ uppel-like factor; MAPK, mitogen-activated protein kinase; MMTV-LTR, mouse mammary tumor virus-long terminal repeat; MT1-MMP, membrane-type 1 matrix metalloproteinase; PDZ, postsynaptic density protein 95, discs large 1, and zonula occludens-1; PTP, protein tyrosine phosphatase; RTK, receptor tyrosine kinase; SH2, Src homology 2; SHIP2, SH2 inositol phosphatase 2; SLAP, Src-like adaptor protein; TCF, T-cell specific transcription factor; TEB, terminal end bud; TNFa, tumor necrosis factor a:Epithelial cells are tightly coupled together through specialized intercellular junctions, including adherens junctions, desmosomes, tight junctions, and gap junctions. A growing body of evidence suggests epithelial cells also directly exchange information at cell-cell contacts via the Eph family of receptor tyrosine kinases and their membrane-associated ephrin ligands. Ligand-dependent and -independent signaling via Eph receptors as well as reverse signaling through ephrins impact epithelial tissue homeostasis by organizing stem cell compartments and regulating cell proliferation, migration, adhesion, differentiation, and survival. This review focuses on breast, gut, and skin epithelia as representative examples for how Eph receptors and ephrins modulate diverse epithelial cell responses in a context-dependent manner. Abnormal Eph receptor and ephrin signaling is implicated in a variety of epithelial diseases raising the intriguing possibility that this cellcell communication pathway can be therapeutically harnessed to normalize epithelial function in pathological settings like cancer or chronic inflammation.