The article reviews the physiological and biochemical complexity of tight junctions (TJs), which are essential for separating tissue spaces and regulating solute movement across epithelial cells. The claudin family of transmembrane proteins is highlighted as the most critical for defining TJ selectivity. The authors discuss the evolution of understanding about TJ function, from early perceptions of them as inert barriers to the current recognition of their complex structure and function. They describe the role of claudins in creating charge-selective pores and the formation of discontinuities in the barrier, which lack charge or size discrimination. The article also covers the physiological relevance of selectivity, the regulation of selectivity, and the impact of mutations in claudins on disease. Despite significant progress, the authors note that further insights are hindered by the lack of high-resolution structural information about TJ proteins.The article reviews the physiological and biochemical complexity of tight junctions (TJs), which are essential for separating tissue spaces and regulating solute movement across epithelial cells. The claudin family of transmembrane proteins is highlighted as the most critical for defining TJ selectivity. The authors discuss the evolution of understanding about TJ function, from early perceptions of them as inert barriers to the current recognition of their complex structure and function. They describe the role of claudins in creating charge-selective pores and the formation of discontinuities in the barrier, which lack charge or size discrimination. The article also covers the physiological relevance of selectivity, the regulation of selectivity, and the impact of mutations in claudins on disease. Despite significant progress, the authors note that further insights are hindered by the lack of high-resolution structural information about TJ proteins.