Malignant melanoma, once metastasized, has a dismal prognosis because of intrinsic resistance to anticancer drugs. First-line therapy includes the methylating agents dacarbazine and temozolomide. Although DNA mismatch repair and O(6)-methylguanine (O(6)MeG)-DNA methyltransferase (MGMT) are key determinants of cellular resistance to these drugs, there is no correlation between these markers and the therapeutic response in melanoma, indicating as yet unknown mechanisms of drug resistance. We show that in malignant melanoma cells with wild-type p53, the temozolomide-induced DNA damage O(6)MeG triggers upregulation of the Fas/CD95/Apo-1 receptor without activating the apoptosis cascade. This is due to silencing of procaspase-8. A single treatment with IFN-β reactivated procaspase-8 and sensitized melanoma cells to temozolomide. The key role of procaspase-8 in melanoma cell sensitization was verified by experiments in which the death receptor pathway was blocked by expression of dominant-negative FADD, siRNA knockdown of procaspase-8, or stimulation with Fas/CD95/Apo-1 activating antibody. The expression of procaspase-8 could further be enhanced by additional pretreatment with the histone deacetylase inhibitor valproic acid (VPA), which together with IFN-β caused significant sensitization of melanoma cells in vitro. Sensitization of melanoma cells to temozolomide by IFN-β and VPA was also shown in a xenograft mouse model. The data provide a plausible explanation why therapy of malignant melanomas with alkylating anticancer drugs failed even in trials where the repair of the critical toxic lesion O(6)MeG was blocked by MGMT inhibitors and suggest approaches to abrogate intrinsic drug resistance by IFN and VPA-mediated reactivation of the death receptor pathway.