Activation of transcription factor NF-kappaB is frequently encountered in tumor cells and contributes to aggressive tumor growth and resistance to chemotherapy and ionizing radiation during cancer treatment. Accumulating evidence over the last few years indicate that most chemotherapeutic agents and radiation therapy activate NF-kappaB in vitro and in vivo. Moreover, induction of chemoresistance and radioresistance is mediated through several genes regulated by NF-kappaB and inhibition of this transcription factor increases sensitivity of cancer cells to the apoptotic action of chemotherapeutic agents and to radiation exposure. This review explores the role of NF-kappaB and its regulated genes in resistance of tumor cells to chemotherapeutic agents and radiation and evaluates the importance of targeting NF-kappaB as a potential therapeutic approach to overcome chemoresistance and radioresistance for cancer treatment.