Photolyases comprise efficient enzymes to remove the major UV-induced DNA lesions, cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). While photolyases are present in all three kingdoms of life (i.e., bacteria, prokaryotes and eukaryotes), placental mammals appear to have lost these enzymes when they diverted from marsupials during evolution. Consequently, man and mice have to rely solely on the more complex and, for these lesions, less efficient nucleotide excision repair (NER) system. To assess the relative contribution of CPDs and 6-4PPs to the cytotoxic and genotoxic effects of the UV component of sunlight, we have recently generated a comprehensive set of transgenic mice expressing CPD and/or 6-4PP photolyases. Here, we discuss the use of photolyase transgenic mice as effective tools to study the adverse effects of UV irradiation.