The tight junction forms a regulated barrier in the paracellular pathway between epithelial and endothelial cells. This intercellular junction also demarcates the compositionally distinct apical and basolateral membranes. While the existence of a paracellular barrier in epithelia was hypothesized by physiologists over a century ago, the molecular characterization of the tight junction is a relatively new and rapidly expanding area of research. It is now recognized that the tight junction is comprised of at least nine peripheral and one integral membrane proteins. This complex includes members of a protein family related to tumor suppression and signal transduction, a rab protein, and a Ras target protein. The characteristics of, interactions between, and potential physiological roles of these proteins at the tight junction are discussed.