This review describes the structure, function, and modulation of E-cadherins as cell-cell adhesion modulators. E-cadherin is a calcium-dependent cell-adhesion protein that is involved in the formation of intercellular junctions, cell morphogenesis, tumor invasion and metastasis, and adhesion of pathogens to the host cells. Structural studies (i.e., NMR, CD and X-ray) show that E-cadherins are exposed on the cell surface as dimmers; a dimmer from one cell interacts (homophilic) with another dimmer from another cell to form a tetramer. It is also found that E-cadherin can form heterophilic interactions with integrin α_Eβ₇ and internalin. The cytoplasmic domain of E-cadherin binds to α-, β-, and γ-catenins; the cadherin-catenin complex regulates the extracellular adhesion function of E-cadherins. Other proteins such as EGFR, Wnt-1, Syndecan-1, HTLV-I Tax protein, IGF-IR, and IL-6 are also involved in the regulation of E-cadherin function. Modulation of E-cadherin expression and function may have many therapeutic applications, including tumor invasion treatment and diagnosis, modulation of intercellular junctions of drug delivery, and inhibition of adhesion of pathogens to host cells. Some of these applications have been proposed and investigated recently; these applications are described here.