The epithelium comprises an important tissue that lines the internal and external surfaces of metazoan organs. In order to organize sheets of epithelial cells into three-dimensional tissues, it requires the coordination of basic cellular processes such as polarity, adhesion, growth, and differentiation. Moreover, as a primary barrier to the external environment, epithelial tissues are often subjected to physical forces and damage. This critical barrier function dictates that these fundamental cellular processes are continually operational in order to maintain tissue homeostasis in the face of almost constant trauma and stress. A protein that is largely responsible for the organization and maintenance of epithelial tissues is the transmembrane protein, E-cadherin, found at the surface of epithelial cells. Though originally investigated for its essential role in mediating intercellular cohesion, its impact on a wide array of physiological processes underscores its fundamental contributions to tissue development and its perturbation in a variety of common diseases.