Differently from the other cells of the body, epidermal cells of the skin undergo a specific programmed cell death form named cornification. Many events take part to control this process, which has been described as a terminal differentiation program. Going from the innermost layer to the outermost, epidermal cells stop dividing, change their shape, acquire new cellular structures and strengthen their cytoskeleton. This is corroborated by the fact that during this physical transition they change their gene expression, reprogramming in some way their biochemical activity. The activation of critical enzymes, including proteases and transglutaminases is a fundamental cellular event. These enzymes are involved in building the supramolecular and cornified structures which confer resistance to the epidermis which carries out a vital function as a skin barrier, preserving the organism from various insults. Here we review current concepts about cornification and the mechanisms by which this process is preserved in species.