Epithelia and endothelia demarcate and regulate transport between tissue compartments in the body. The tight junction contributes to two central aspects of epithelial and endothelial physiology. First, the tight junction constitutes the principal barrier to passive movement of fluid, electrolytes, macromolecules and cells through the paracellular pathway (the ‘‘gate’’function, Diamond, 1977). This pathway is defined as the space between cells made up of the tight junction and lateral intercellular space in series (Fig. 1). It is now abundantly clear that the tight junction is not a simple gasketlike barrier. The tight junction demonstrates ion selectivity, varies significantly in permeability between different tissues, may be subject to physiological regulation, and undergoes dynamic modulation upon passage of cells of the immune system from one tissue compartment to another (reviewed in Madara et al., 1992). Second, the tight junction may contribute to epithelial transport by promoting epithelial cell surface polarity. By restricting free diffusion of lipids and proteins in the plane of the plasma membrane (the ‘‘fence’’function, Diamond, 1977) the tight junction may help maintain the distinct apical and basolateral surface compositions necessary for vectorial transport across epithelia (Gumbiner, 1990). Despite the physiological importance of tight junctions, relatively little is known about the molecular and cellular mechanisms that underlie tight junction physiology. Based on macroscopic conductance and sieving properties of epithelia and the ultrastructural appearance of the tight junction, it has been hypothesized that the tight junction contains size-and charge-selective aqueous channels or pores formed by integral membrane proteins that otherwise act to occlude the extracellular space (Cereijido et al., 1989; Madara et al., 1992; Reuss, 1992). Such channels would allow the selective passage of ions, but not macromolecules or cells. In addition, it has been proposed that continuous chains of these integral membrane proteins prevent passive diffusion of plasma membrane constituents (Pisam & Ripoche, 1976). Attractive as these models may be, direct proof of such channelcontaining integral membrane proteins has yet to emerge. However, significant progress has been made in characterizing the molecular constituents of the tight junction in the last decade. Ultimately, the aim of such research is to define the molecular mechanisms responsible for all aspects of tight junction function. In particular, there has been an intense search for the integral membrane protein (or proteins) that mediate the gate and fence functions of the tight junction. Recent attempts to study one such candidate molecule, occludin, have provided intriguing insights into, and paradoxes concerning, the molecular physiology of the tight junction.