Nonmelanoma skin cancers are among the most common human malignancies. Although typically not lethal, they are responsible for tissue deformity and substantial morbidity, particularly in high-risk populations. Solar UVB radiationa major etiologic factor for this kind of malignancyproduces DNA lesions such as cyclobutane pyrimidine dimers and 6-4 photoproducts in skin. These lesions are removed through nucleotide excision repair because humans lack a DNA glycosylase required to initiate base excision repair of pyrimidine-pyrimidine photoproducts but produce all the other proteins required for this process. In this issue, Johnson et al. show that a DNA glycosylase derived from Chlorella virus and engineered to enhance tissue penetration and nuclear localization can remove UVB-induced DNA lesions in a human skin equivalent model and that the protein can be incorporated into a topical formulation for the prevention and treatment of UVB-induced DNA damage. These results suggest that such an enzyme may be incorporated into regimens for the chemoprevention of skin cancers. © 2011 The Society for Investigative Dermatology.