Tight junctions of epithelial and endothelial cells form selective barriers that regulate paracellular transport of solutes, immune cells, and drugs. Tight junctions consist of proteins that physically "seal" the tight junction but also form channels that allow for permeation between the cells, resulting in epithelial surfaces of different tightness. The tight junction proteins occludin, tricellulin, and at least 24 members of the claudin family are characterized by four transmembranal domains and two extracellular loops that, like teeth of a zipper, contact the appropriate loops from opposing cell membranes. Tight junctions are regulated in their molecular composition, ultrastructure, and function by intracellular scaffolding proteins and the cytoskeleton; such regulation serves normal, physiologic adaptation but also occurs in numerous diseases.