Epithelial cells exhibit an apical–basolateral axis of polarity that is generated during embryogenesis, is maintained throughout adult life in the face of constant cell regeneration, and is perturbed in several epithelial-associated diseases. We examine the structural and functional organization of epithelial tissues, as well as the events critical for generating epithelial asymmetry including vectorial trafficking of proteins and lipids, association of signaling and polarity proteins with subdomains of the plasma membrane, and 3D orientation of epithelial cells in response to cell–cell and cell–matrix interactions. As a paradigm to understand how these three processes are coordinated in time and space, we explore apical lumen formation. We also examine the final steps in epithelial morphogenesis, including brush border morphogenesis and ciliogenesis. Finally, we provide examples of disease processes that result from defects in epithelial polarity including diabetes insipidus, microvillar inclusion disease, hereditary deafness, ciliopathies, and cancer.