Unlike 13-cis retinoic acid, the synthetic retinoid fenretinide induces apoptosis of neuroblastoma cells and in vitro acts synergistically with the chemotherapeutic drugs, cisplatin, etoposide and carboplatin. The stress-induced transcription factor GADD153 and the Bcl2-related protein Bak are upregulated in response to fenretinide. Although fenretinide is a partial retinoic acid receptor (RAR)-beta/gamma agonist, RARbeta/gamma antagonists do not block the induction of GADD153 or Bak by fenretinide. Conversely, the induction of GADD153 and Bak is blocked by antioxidants. Neither GADD153 or Bak were induced by chemotherapeutic agents but over expression of GADD153 results in increased sensitivity to fenretinide-induced apoptosis. Therefore, fenretinide induces apoptosis via RAR-dependent and -independent pathways in which the RAR-independent pathway is characterised by the reactive oxygen species-dependent induction of GADD153 and Bak. The targeting of GADD153 and Bak in neuroblastoma cells may be novel pathways for the development of drugs inducing apoptosis of neuroblastoma with improved tumour specificity.