The terminal differentiation of epidermal keratinocytes has been regarded as an example of programmed cell death. Among the proteins specifically expressed in this process is profilaggrin, which consists offilaggrin repeats and N- and C-terminal domains. Profilaggrin is proteolytically processed into individual domains during the terminal differentiation. Filaggrin released from profilaggrin aggregates keratin filaments to form compacted cornified cells with a keratin pattern. A recent transfection experiment has indicated initiation of cell death by filaggrin expression constructs. The transitional cells between the granular and cornified cells show morphologic characteristics of apoptotic cells, and their nuclei contain fragmented DNA and profilaggrin N-terminal domains. This suggests that the N-terminus of profilaggrin may participate in nuclear events accompanying programmed cell death. Among inherited skin disorders with abnormal keratinization, progressive symmetric erythrokeratoderma is caused by loricrin mutation (loricrin keratoderma). In this disease, profilaggrin N-terminal domains are aggregated with mutant loricrin within condensed nuclei. These nuclei persist in the cornified layer as parakeratosis. Loricrin keratoderma could therefore be regarded as a representative form of disrupted cell death.