Warner-Lambert/Parke-Davis Award lecture. Pathobiology of the intestinal epithelial barrier. The major route of passive permeation across intestinal epithelia is paracellular. The intercellular tight junction lies in and serves as the rate-limiting barrier in this paracellular pathway. Once viewed as static, it is now clear that the structure and permeability of the tight junction is highly dynamic. Not only may inflammatory events (cytokines, neutrophil transmigration) reversibly effect the tight junction but this key barrier also is regulated by physiologic events such as activation of absorptive cell Na(+)-nutrient cotransporters. Such physiologic regulation of the junction is of major importance to the absorption of nutrients via parcellular solvent drag. 