Significant progress has been made over the past decade in understanding the role of claudins in regulation of TER and paracellular ionic selectivity. In addition, the recognition of the existence of two pathways for paracellular solute flux should allow a more sophisticated analysis of the roles individual TJ proteins play in physiologic and pathologic regulation of permeability of nonionic solutes. However, further insights are hampered by the lack of a three-dimensional model of TJ structure. Studies on the synaptic junction may provide clues and methods for studying TJ organization, but ultimately we will need structural information about the integral membrane proteins of the TJ to ask informative questions about how this complex is organized and physiologically regulated.