Epithelial cells must be closely apposed and form tight junctions with one another if they are to maintain a different composition in the extracellular fluid at their apical and basolateral sides. Tight junctions provides a physical block to solute diffusion around cells, and freeze fracture electron microscopic images of these structures reveal multiple parallel strands that extend along the cell surface and contact the neighboring cell. However, tight junctions do not simply provide a gasket around each cell but rather block the flow of different classes of solutes selectively and in characteristic ways in different epithelia. Here, Van Itallie et al. argue that these functional differences arise from differential expression of claudins, transmembrane proteins that localize to the tight junction. Claudin-4 is normally found in the pancreas and in certain cells of the colon, but the authors use an inducible promoter to drive expression of this protein in MDCK cells, a well studied model epithelial cell line. They find that as claudin-4 levels rise, the number of strands seen in microgaphs of the tight junction increases and the paracellular flow of Na+ ions and of other monovalent cations declines . Remarkably, however, transport of uncharged or anionic solutes is unchanged. The molecular and structural basis of this selectivity remains a puzzle.