To survive the transition from an aqueous in utero to a terrestrial ex utero environment, mice and humans must construct an epidermal permeability barrier in utero. Terminally differentiated epidermal cells, lipids and tight junctions are all essential to achieve this barrier. Recent analyses of mouse mutants with defects in structural components of the terminally differentiated epidermal cell, catalyzing enzymes, lipid processing, transcriptional regulators and the intercellular junctions have highlighted their essential function in establishing the epidermal permeability barrier. Particularly interesting examples include modulation of the expression of transglutaminase 1 enzyme, the transcription factor Klf4 and the claudin tight junction proteins. However, careful analysis of the various mutant phenotypes during embryonic development, as neonates and either as adults or transplanted skin, has revealed much more about the redundancy and compensatory mechanisms of the system. Molecular analysis of the various mouse mutants has demonstrated common pathways to compensate for loss of the epidermal barrier.