In higher organisms, epithelia separate compartments in order to guarantee their proper function. Such structures are able to seal but also to allow substances to pass. Within the paracellular pathway, a supramolecular structure, the tight junction transport is largely controlled by the temporospatial regulation of its major protein family called claudins. Besides the fact that the expression of claudins has been identified in different forms of human diseases like cancer, clearly defined mutations in the corresponding claudin genes have been shown to cause distinct human disorders. Such disorders comprise the skin and its adjacent structures, liver, kidney, the inner ear, and the eye. From the phenotype analysis, it has also become clear that different claudins can cause a complex phenotype when expressed in different organs. To gain deeper insights into the physiology and pathophysiology of claudin-associated disorders, several mouse models have been generated. In order to model human disorders in detail, they have been designed either as full knockouts, knock-downs or knock-ins by a variety of techniques. Here, we review human disorders caused by CLDN mutations and their corresponding mouse models that have been generated thus far and assess their usefulness as a model for the corresponding human disorder.