Tight junctions (TJ) are intercellular seals that regulate the passage of ions and molecules through the paracellular pathway. This property allows epithelial and endothelial sheets to function as barriers between different body compartments. Although TJ were identified by electron microscopy since the 1950's, the analysis in recent years of their molecular composition, has depicted TJ as signaling complexes involved in a wide spectrum of physiological and pathological processes, such as cell growth and differentiation, cancer and metastasis, and pathogen interaction. This new knowledge has in turn given rise to novel strategies for enhancing the paracellular flux of poorly absorbed therapeutics.