Exposure of normal adult human skin to doses of UV irradiation that induced mild sunburn resulted in the rapid appearance of p53 protein in the epidermis and superficial dermal fibroblasts. Immunohistological analysis with a panel of antibodies established that while p53 staining was not seen in normal skin it appeared within 2 h of UV exposure. The level of p53 immunostaining peaked at 24 h and returned to undetectable levels within 360 h. The induction of proliferating cell nuclear antigen (PCNA) (which is required for both DNA replication and repair) followed a similar spatial and temporal pattern to p53. The UV irradiation did not induce a mitotic response or the replication-associated antigens DNA polymerase alpha or Ki67. The accumulation of high levels of p53 and PCNA in response to UV doses to which many human populations are routinely exposed provides strong support for a model in which normal p53 acts as part of the DNA damage response in vertebrate cells. Such a model is consistent with the profound tumour-suppressor function of the p53 gene, the high rate of p53 mutation in neoplasia and the exceptionally high tumour susceptibility of p53-deficient mice.