Study of the structure and regulation of tight junctions in epithelia and endothelia is one of the fastest growing areas in biomedical research, represented at every national meeting of not only physiology and cell biology, but also nephrology, gastroenterology, pulmonary biology and even reproductive biology and neuroscience. The discovery of tight junctional-associated proteins in the 1980s and integral membrane tight junction proteins in the 1990s has catalyzed these investigations. However, the underlying force behind this explosive literature is the enormous biomedical significance of tight junction permeability and epithelial barrier function. The ability to separate fluid compartments in vivo, be it blood from urine or blood from cerebral spinal fluid is perhaps the most basic feature of higher life forms. It is a supremely basic biological theme that can be witnessed ontologically in the blastula or phylogenically in the sea anemone. Its breakdown, even partially, may form the underlying basis of a host of human diseases, with chronic inflammatory diseases and epithelial cancer being prominent examples. In this review we hope to highlight what we feel are likely areas of future emphasis in tight junction research, based upon past research and the diseases where pathophysiology of tight junction permeability appears to play a role. These areas are: 1) continued delineation of tight junction structural proteins, with an emphasis on signal transduction pathways controlling tight junction permeability; 2) the ability of cytokines to compromise epithelial barrier function, and the issue of apoptosis of epithelial cells in an epithelial barrier; and 3) the increase of tight junction permeability early in epithelial neoplasia, and the possible diagnostic/therapeutic significance of these leaks.