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Cultured epithelial autografts offer an exciting approach to cover extensive skin wounds. The main problem of this method is mechanical instability during the first weeks after grafting. There is evidence that the shortcomings of autografting cultured keratinocytes result from the lack of a mature and functional dermo-epidermal junction. This article summarizes the current knowledge regarding the de novo formation of the dermo-epidermal junction and the dynamics of "take" and stabilization of cultured epithelial autografts. Future strategies are discussed of how to improve and accelerate the process conferring definitive stabilization of cultured epithelial autografts including the potential therapeutic use of transglutaminase as well as cocultivation of a dermo-epidermal equivalent in order to facilitate a permanent skin replacement.