The p53 gene (TP53) is mutated in numerous human cancers. We have used it as a molecular target to characterize the induction of mutations in human skin cancers. About 50% of all skin cancers in normal individuals exhibit p53 mutations. This frequency rises to 90% in skin cancers of patients with the DNA‐repair deficiency known as xeroderma pigmentosum (XP). These mutations are characterized by a specific signature, attributed to the ultraviolet uvB part of the solar spectrum. In this review, we will describe different p53 mutation spectra, in relation to the various histopathological types of skin cancers such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and malignant melanoma as well as to the DNA repair efficiency of the patients. In particular, different mutational hot spots are found among the various spectra. We have tried to elucidate them in terms of induced DNA lesion hot spots, as well as speed of local nucleotide excision repair (NER) or sequence effects. The molecular analysis of these mutagenic characteristics should help in the understanding of the origin of human skin cancers in the general population. Hum Mutat 21:217–228, 2003. © 2003 Wiley‐Liss, Inc.