We have investigated the effect on the normal synthesis and metabolism of filaggrin of treatment of guinea pig skin with a chemical irritant, hexadecane, or with erythemal doses of UV radiation. Examination of the skin by immunofluorescence with an antiserum against filaggrin demonstrates 3 phases of the response. The first phase is an apparent stabilization of the filaggrin present at the time of treatment. Thus, a zone of stratum corneum is produced which moves up toward the skin surface over the days following treatment, without the loss of immunoreactivity which normally results from the metabolism of filaggrin to free amino acids. The second phase of the reaction, which occurs during the first day after treatment, is a loss of immunoreactive material from the upper viable epidermis, which results over the next day in the formation of a zone of filaggrin-deficient stratum corneum. The third phase, 2-3 days after the treatment, is the reestablishment of immunoreactivity in the newly re-formed granular layer, followed by the formation of an immunoreactive zone at the bottom of the stratum corneum. This zone remains very thin despite the rapid passage of cells through it. This shows that the filaggrin being formed during this phase of the reaction is being broken down normally as the stratum corneum matures. Investigations of the kinetics of filaggrin synthesis and breakdown using a [3H]histidine pulse/chase method, confirm the impression gained from immunofluorescence studies that the time between formation and breakdown of the filaggrin is much reduced in the hyperplastic epidermis resulting from the irritation. Thus, although the hyperplasia is reflected in a thickening of malpighian and granular layers of the epidermis, it does not result in any thickening of the filaggrin-positive zone at the bottom of the stratum corneum. This suggests the action of a control mechanism designed to prevent the extension of this filaggrin-positive zone into the upper stratum corneum.