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The epidermis is part of the innate immune system and represents the first line of defense against external insults. It must continuously replace differentiated or damaged keratinocytes, and this is maintained through a multilayered structure and a dynamic equilibrium between proliferation of stem cells and transit-amplifying cells in the basal layer and differentiation in suprabasal layers. At the surface of the epidermis, keratinocytes die by a specific and well-orchestrated terminal differentiation process, and the resulting dead corneocytes play an essential function as the first barrier against the environment. New evidence demonstrates that keratinocyte-specific ablation of the apoptotic caspase-8 in mice destroys the balance in the epidermis. Although differentiation in the outermost epidermal layers of these mice is normal, the mice suffer from strong cutaneous inflammation because of enhanced production and secretion of the proinflammatory cytokine pro-interleukin-1α.