Non-melanoma skin cancers (NMSC), namely basal cell carcinomas (BCC) and squamous cell carcinomas (SCC), represent the most common form of malignancy in fairskinned populations. Solar ultraviolet radiation (UVR), immunosuppression, and genetic constitution of the host are well-known risk factors for the development of NMSC. Epidermodysplasia verruciformis (EV), a rare genetic disease associated with a high risk of skin cancer, provided the first clue to a possible role of viruses in human skin carcinogenesis (Jablonska et al, 1972). Due to mutations in either of the related EVER1 and EVER2 genes, EV patients are abnormally susceptible to a specific group of related human papillomavirus genotypes (known as EV HPV) and to the oncogenic potential of some of these viruses (Orth, 1987; Ramoz et al, 2002). EV HPV cause widespread, inapparent infections in the general population (Antonsson et al, 2003). In EV patients, however, infection leads to persistent wartlike and macular skin lesions, and premalignant lesions and SCC develop on sun-exposed areas of the skin in about half of the patients. EV SCC harbor high copy numbers of episomal HPV genomes (HPV5 or occasionally HPV8, 14, 17, 20, or 47) and abundant transcripts of the E6 and E7 genes. Phenocopies of EV are exceptionally observed in immunosuppressed patients. EV is thus a rare experiment of nature that provides a model for studying the interaction among potentially oncogenic HPV genotypes, UVR, immunity, and genetic factors (Orth, 1987). EV HPV DNA sequences have only rarely been detected in cutaneous premalignant tumors and NMSC in non-EV patients by Southern blot hybridization, which is sensitive enough to detect one HPV genome per cell. Using highly sensitive PCR approaches, however, HPV DNA sequences were detected in 25%–65% of NMSC in immunocompetent individuals and in up to 90% of SCC in organ transplant recipients (OTR), a population at a greatly increased risk of developing SCC. Similar HPV detection rates were found for actinic keratoses (AK), the precursor lesion of SCC (reviewed in Forslund et al, 2004). These data led researchers to consider a role for HPV, especially EV HPV types, in the development of NMSC (Orth, 2004). Available epidemiological and seroepidemiological data provide some support to an association between the presence of EV HPV DNA in normal skin or eyebrow hairs or the seroreactivity to some EV HPV and an increased risk of AK and SCC (reviewed in Purdie et al, 2005; Weissenborn et al, 2005). The link between EV HPV and the development of NMSC in immunocompetent and immunosuppressed individuals, however, remains unclear (reviewed in Orth, 2004). EV HPV and non-EV cutaneous HPV types represent impressively diverse, ubiquitous viruses, which are highly prevalent in the normal skin of healthy adults (Antonsson et al, 2003). A great diversity of cutaneous HPV types, most frequently EV HPV or putative novel EV HPV-related types, is detected in AK and NMSC, and mixed infections are frequently observed in tumors of OTR patients. Furthermore, it has recently been shown that cutaneous HPV DNA is common on top of AK, SCC, and BCC but less prevalent (3.2–7.9-fold) in ‘‘stripped’’tumors, suggesting that HPV DNA positivity may reflect, in part, contamination of the surface of the tumors by viral DNA or particles shed from infected healthy skin (Forslund et al, 2004). It should be also stressed that the tumor HPV DNA loads are usually low and that it remains unknown whether the viral sequences are transcriptionally active. The articles by Weissenborn et al (2005) and by Purdie et al …