First line therapy in the treatment of gliomas and malignant melanomas are alkylating agents.These agents induce a dozen of different DNA damages, some of them have been identified to be carcinogenic, genotoxic, recombinogenic and cytotoxic.An important DNA damage induced by methylating drugs is O6-methylguanine (O6MeG).This damage causes mutations and is responsible for most of the carcinogenic effects of alkylating drugs.The damage is repaired by the suicide enzyme alkyltransferase (MGMT), which is considered to be a very important marker of drug resistance in gliomas.For malignant melanomas the situation is less clear; very likely other mechanisms of alkylation drug resistance come into play as well such as mismatch repair.O6MeG is a potent trigger of the programmed cell death (apoptosis) pathway.We have studied in detail how apoptosis induced by O6MeG is executed in glioma and melanoma cells.We have shown that cell death is executed both via the death receptor and the mitochondrial damage pathway, with DNA double-strand breaks (DSB) to be involved.The efficiency of O6MeG to trigger the p53 dependent death receptor pathway is higher than the p53 independent endogenous mitochondrial pathway, which explains why p53 wt glioma cells are more sensitive to temozolomide than p53 mutated cells.