Cholangiocarcinoma (CCA) is one of the most devastating malignancies because the majority of cases develop without clinical symptoms, and thus making the diagnosis of CCA very difficult. Prognosis of CCA is extremely poor because treatment outcomes and survival of the patients have only slightly improved in the past several decades. Because most of patients are already in the advanced stage of the disease at diagnosis, chemotherapy and radiotherapy may be the options left for most patients. However, no effective chemotherapy is known for CCA. The study was to provide evidence น to support a new strategy for enhancing cancer cell killing by mean of inhibition of antioxidant/cytoprotective enzymes and increase of cellular oxidantsin cancer cells. The study reviewed that inhibition of heme oxygenase-1 (HO-1) or NADPH quinoneoxidoreductase-1 (NQO1) resulted increased cellular oxidant and conferred a strong sensitizing effect to CCA cells in response to chemotherapeutic agents. The study was verified by knockdown of HO-1 or NQO1 gene expression. Inhibition of HO-1 also sensitized CCA cells to gamma radiation, where colony forming ability was impaired and cell cycle was arrested at G2-M phase. The antiproliferation of Zn-protoporophyrin (ZnPP), a potent HO-1 inhibitor, in combination with gemcitabine (Gem) was causally associated with oxygen radical formation. The study was validated in nude mice xenografted with CCA cells. Treatment with ZnPP, in combination with (Gem) almost completely arrested the tumor growth, while single treatment did not. The effect was associated with suppression of tumor cell proliferation and angiogenesis, and with activation of p53. Moreover, the role of NQO1 in CCA patients was investigated and showed to be a good prognostic biomarker. As the level of NQO1 mRNA expression was inversely correlated with patient survival, the higher NQO1 expression, the shorter survival time found in the patients. The study of phenethyl isothiocyanate (PEITC), a phytochemical known for its inducer of cellular oxidants found in cruciferous vegetables, was shown that it potently inhibited growth of several CCA cells and induced apoptotic cell death. The effects of PEITC on the cellular redox are mediated via different ways in different CCA cells leading to cell killing through the mitochondrial pathway. The multiple effects of PEITC may be beneficial in overcoming the drug resistant cancer cells. The study demonstrated a proof of concept of approach to enhanced chemo/radiotherapy response by interference with antioxidant/ cytoprotective system of the cancer. Our studies indicated the synergistic effect of HO-1 inhibition in chemotherapy and radiotherapy and it may be true for NQO1 inhibition. This worthy strategy warrants further investigation in the treatment of CCA.