Tight junctions (TJ) are barrier forming cell-cell junctions that are found in a variety of cell types and tissues but their existence in mammalian epidermis has been shown only in the last years. A variety of TJ proteins were identified in mammalian epidermis, comprising several members of the claudin family, occludin, and JAM-A as well as ZO-1 and MUPP-1. TJ proteins exhibit complex expression and localization patterns in the epidermis. Nonetheless, even though several TJ proteins are found in various layers, typical TJ structures are only found in the stratum granulosum. TJ are important for barrier function of the skin, especially for inside-out barrier. In addition, TJ proteins might also be involved in additional functions in epidermal cells. Localization and expression of TJ proteins are altered in several skin diseases, e.g. psoriasis. Meanwhile several TJ modulators are known from simple epithelia. We discuss their putative usability for drug delivery into and through the skin.