Resistance of tumors to cytotoxic therapy remains a major obstacle in cancer treatment and is often caused by defects in apoptosis programs. Caspase-8, a key mediator of death receptor-induced apoptosis, has previously been reported to be frequently inactivated by epigenetic silencing in many tumors, for example in neuroblastoma or medulloblastoma. Here, we provide for the first time evidence that combined treatment with suboptimal concentrations of the demethylating agent 5-Aza-2'-deoxycytidine (5-dAzaC) and interferon-gamma (IFN-gamma) cooperated to upregulate caspase-8 expression in neuroblastoma and medulloblastoma cells lacking caspase-8. Consequently, activation of caspase-8 and downstream caspases upon addition of TNF-related apoptosis-inducing ligand (TRAIL) was restored by pretreatment with 5-dAzaC and IFN-gamma. Importantly, pretreatment with 5-dAzaC and IFN-gamma acted in concert to significantly enhance TRAIL-induced apoptosis in neuroblastoma and medulloblastoma cells. Inhibition of caspase-8 by dominant-negative caspase-8 or by the relatively specific caspase-8 inhibitior zIETD.fmk inhibited the increase in apoptosis provided by 5-dAzaC and IFN-gamma, indicating that caspase-8 is a key mediator of this sensitization effect. Thus, by demonstrating that 5-dAzaC and IFN-gamma at relatively low individual concentrations cooperate to restore caspase-8 expression and sensitize resistant neuroblastoma and medulloblastoma cells to TRAIL-induced apoptosis, our findings have important implications for novel strategies targeting defective apoptosis pathways in neuroectodermal tumors.