Tight junction (TJ) composes of an intriguing class of cell junction molecules, for which these molecules share similar organizations and structure features among different organs. Fourtypes of transmembrane molecules namely occludins, claudins, junctional adhesion molecules and coxsackievirus and adenovirus receptors act as core units and each link directly and indirectly with a panel of peripheral molecules and underlying cytoskeletons to constitute the functional protein complexes at TJs. Individual TJ complex alone or in co-operation with other complexes via cross-talk mediated by peripheral molecules activate signaling pathways pertinent to various physiological and pathological processes in livers. In human livers, TJs are located at two regions in association with hepatocytes and cholangiocytes and perform major roles in controlling bile flow and metabolism. Apart from this physiological function, the other functions of TJs relating to liver diseases of hepatitis and liver cancer are gradually uncovered. The understanding of how TJs are involved in these clinical conditions hint for the development of new treatments at the molecular level.