Previous investigations have demonstrated that isogenic cutaneous squamous cell carcinoma cell lines (cSCC), isolated from highly dysplastic skin (PM1), primary invasive SCC (MET1) and its lymph node metastasis (MET4), show an increasing resistance to cisplatin-induced apoptosis in the increasingly malignant MET1 and MET4 cells. To investigate whether cell death sensitivity in progressive stages of skin carcinogenesis is dependent on the kind of stress we examined the sensitivity of PM1, MET1 and MET4 cells to apoptosis in response to a single UVB-dose (mixture of genotoxic and oxidative stress), or to hydrogen peroxide and hypericin photodynamic treatment (both pure oxidative stresses). MET1 cells, followed by the MET4 cells, were more sensitive to UVB, resulting in more cell death and more apoptosis in comparison with the PM1 cells. A similar pattern of sensitivity was observed when we exposed the SCC cells to hydrogen peroxide or hypericin photodynamic treatment, which both generate mainly oxidative stress. The MET1 cells were the most sensitive to all stresses examined. The pattern of cell death sensitivity in a model of progressive cutaneous squamous cell carcinoma is dependent on the kind of stress. While more advanced skin cancer cells like MET1 and MET4 cells lose their sensitivity to the chemotherapeutic agent cisplatin, they remain sensitive to hydrogen peroxide or physical treatments, which induce major oxidative stress. This differential sensitivity could have implications for the treatment of advanced cSCC.