Ultraviolet B (UVB) light is the principal aetiological factor associated with non-melanoma skin cancer, the most prevalent group of malignancies in the Caucasian population. Exposure to environmental chemicals has also been shown to promote skin carcinogenesis and, as for UVB, this is associated with the acquisition of genomic DNA damage. Cells respond to DNA damage by inducing cell cycle arrest to facilitate DNA repair, although apoptosis will occur if the damage is excessive. Oncogenes may drive carcinogenesis by disrupting the balanced control of cell cycle progression, DNA repair and apoptosis, allowing for the propagation of cells with damaged DNA. The transcription factors GLI1 and GLI2 have been implicated in both the initiation and progression of several cancers, including basal cell carcinoma. Here we show that GLI1 and an active mutant of GLI2 (ΔNGLI2) promote apoptotic resistance in N/TERT human keratinocytes upon exposure to UVB and the DNA-alkylating chemicals such as methyl methanesulphonate (MMS) and N-ethyl-N-nitrosurea. Compared with control and untreated N/TERT-GLI1 and -GLI2 cells, those that survived genotoxic insult formed significantly more colonies in soft agar and were significantly more invasive when grown in threedimensional organotypic collagen gel cultures. Indeed, surviving N/TERT-GLI1 and -GLI2 cells expressed higher levels of the epithelial-to-mesenchymal transition markers Snail and vimentin, and a subpopulation of MMS-treated cells displayed an elongated fibroblast-like morphology with decreased levels of E-cadherin. Finally, whereas Bcl2 was strongly increased in N/TERT-GLI2 cells, the level of induction was weak in N/TERT-GLI1 cells, indicating that GLI1 may activate anti-apoptotic mechanisms(s) independently of Bcl2. In summary, our results show that GLI1 and GLI2 facilitate the propagation of cells with damaged DNA, and thus their expression may be naturally higher in cells that form the earliest precursor tumour lesions.