Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) selectively induces apoptosis in most tumor cells, a process sometimes potentiated by chemotherapeutic drugs or cycloheximide (CHX). Childhood neuroblastoma (NB) is a clinically and biologically heterogeneous neoplasm whose behavior can be explained by differential regulation of apoptosis. The non‐invasive S‐type NB cell lines are sensitive to TRAIL, whereas the invasive N‐type NB cell lines are resistant. We have reported the silencing of caspase‐8 expression in N‐type cells as a possible mechanism of death receptor‐mediated resistance to apoptosis in NB. The recently observed deregulation of caspase‐10 in these cells prompted us to investigate the particular contribution of caspase‐8 silencing in the resistance to TRAIL in N‐type cells. Stable caspase‐8 expression was therefore restored in the IGR‐N91 cell line by retroviral infection. The IGR‐N91‐C8 cells became sensitive to TRAIL‐mediated apoptosis, whereas the control vector‐infected IGR‐N91‐M cells remained resistant. Interestingly, the apoptotic response to TRAIL was enhanced by co‐treatment of SH‐EP and IGR‐N91‐C8 cells with CHX or with sub‐toxic concentration of doxorubicin (DOX) in a caspase‐dependent manner, as cells could be protected from death by specific caspase‐8 or pan‐caspase inhibitors. CHX or DOX was shown to enhance TRAIL‐induced caspase‐8 activation and loss of mitochondrial transmembrane potential. In conclusion, restoration of active caspase‐8 expression in caspase‐8‐ and caspase‐10‐deficient IGR‐N‐91 cell line is necessary and sufficient to fully restore TRAIL‐mediated cell death. Moreover, DOX and CHX were able to sensitize NB cell lines to TRAIL‐induced apoptosis in a caspase‐8‐dependent manner by engaging death receptor and mitochondrial signaling pathways.