XERODERMA pigmentosum patients with a defect in the nucleotide-excision repair gene XPA are characterized by, for example, a >1,000-fold higher risk of developing sunlight-induced skin cancer(1-3). Nucleotide-excision repair (NER) is involved in the removal of a wide spectrum of DNA lesions, The XPA protein functions in a pre-incision step, the recognition of DNA damage(4-7). To permit tile functional analysis of the XPA gene in vivo, we have generated XPA-deficient mice by gene targeting in embryonic stem cells, The YPA(-/-) mice appear normal, at least until the age of 13 months, XPA(-/-) mice are highly susceptible to ultraviolet (UV)-B-induced skin and eye tumours and to 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin tumours, We conclude that the XPA-deficient mice strongly mimic the phenotype of humans with xeroderma pigmentosum.