The human body maintains maximal independence from the environment by means of a highly impermeable continuous cell sheet. For the maintenance of homeostasis, tight junctions must strictly regulate or restrict the passage of various solutes through the paracellular spaces of the cell sheet. Furthermore, it is clear that tight junctions are deeply involved in signal transduction and innate immunity. When tight junctions are disturbed, illnesses such as edema, jaundice or diarrhea will rapidly develop. In this review, we describe the basic understanding of tight junctions and then introduce our studies on the roles of tight junctions in human diseases such as diabetic retinopathy.