Compared with other types of tumours, malignant melanomas are highly refractory to radio- or chemotherapy. To support the search for possible sensitizers, we explored the effects of the cellular oncoproteins c-Myc and N-Ras, which can decrease the clonogenic potential of irradiated p53-negative IGR39D melanoma cells. Using stable transfectants of this cell line, we showed that mutant N-Ras decreased the proliferation rate by inducing a prolonged cell cycle arrest. In contrast, c-Myc made these melanoma cells more prone to radiation-induced cell death. Membrane blebbing, the formation of apoptotic bodies and caspase activation, as measured by cleavage of Asp-Glu-Val-Asp (DEVD) substrate and poly(ADP-ribose) polymerase (PARP), indicate that these cells die by an apoptotic process. c-Myc also sensitized these p53-deficient melanoma cells to treatment with various cytotoxic drugs and heat shock. Similar results were obtained in inducible c-Myc models of IGR39D and in another melanoma cell line, 9007, which expresses functional p53. Together, these findings indicate that c-Myc is capable of sensitizing typically resistant tumour cells and that this occurs irrespective of the functional status of the p53 protein. Our results should facilitate the identification of factors that can be exploited for the treatment of aggressive cancers.