An important function of the skin is to serve as a barrier. To fulfill this function keratinocytes undergo a complex pathway of differentiation which terminates in the formation of the uppermost cornified layer, the stratum corneum. Additionally, tight junctions (TJs), which are localized directly beneath, in the stratum granulosum, are involved in the barrier function of the skin. Both, the formation of TJs and differentiation are induced by calcium. Up to now it is not clear whether changes seen for TJs in skin diseases or during development might be cause or consequence of altered differentiation, so that the chicken-egg-question arises. Here we show several lines of evidence that alterations of TJs can arise independently or might even be the origin of changes in differentiation. (1) For the skin disease psoriasis we found that altered TJ function in the epidermis occurs independently from the alteration of differentiation. (2) Cldn1-deficient humans show alterations of differentiation i.e. they develop an ichthyosis and knock-down of Cldn-1 in keratinocytes results in an alteration of differentiation markers. (3) CD44 deficient mouse skin as well as cultured keratinocytes derived therefrom show more pronounced and temporarily preceding alterations of TJ proteins compared to markers of differentiation. (4) Treatment of skin with IL-1ß and TNFa results in a short term alteration of markers of TJs but not of differentiation. Therefore our data suggest that expression and localization of TJ proteins as well as formation of TJs might be independent of or even involved in differentiation processes.