The epidermis has evolved to provide a barrier against the environment, which is essential for survival. This barrier is constituted and continuously regenerated by terminally differentiating keratinocytes. Here, we summarize the main features of the response to UVB and oxidizing agents of human keratinocytes and compare it with that of fibroblasts. Keratinocytes are more resistant to the lethal effects of UVB than fibroblasts and remove cyclobutane pyrimidine dimers (CPD) more efficiently than fibroblasts. UV photoproducts are repaired by the nucleotide excision repair (NER) system by two distinct sub-pathways: global genome repair (GGR) that repairs lesions on the genome overall, and transcription coupled repair (TCR) that operates on transcribed sequences of active genes. By using NER-defective cells we demonstrated that the improved repair of UVB damage by keratinocytes is due to a more efficient GGR. A defect in TCR was associated with a strong apoptotic response in fibroblasts but not in keratinocytes, whereas a defect in GGR had no effect on the apoptotic response of either cell type. We speculate that the persistence of CPD in the transcribed sequences triggers apoptosis in fibroblasts but not in keratinocytes where GGR operates as back-up system to remove transcription-blocking lesions. As observed for UVB, keratinocytes are also more resistant to the lethal effects of oxidizing agents than fibroblasts. We show that keratinocytes are characterized by a strong anti-oxidant capacity and a higher susceptibility to reactive oxygen species (ROS)-induced apoptosis than fibroblasts. All together these results provide a clear evidence that the response to environmental agents is strongly affected by the type of damage as well as by the cellular background.