NF-kappaB transcription factor regulates important cellular processes ranging from establishment of the immune and inflammatory responses to regulation of cell proliferation or apoptosis, through the induction of a large array of target genes. NF-kappaB is now considered as an important actor in the tumorigenic process mainly because it exerts strong anti-apoptotic functions in cancer cells. NF-kappaB is triggered by chimio- and radio-therapeutic strategies that are intended to eliminate cancerous cells through induction of apoptosis. Numerous studies have demonstrated that inhibition of NF-kappaB by different means increased sensitivity of cancer cells to the apoptotic action of diverses effectors such as TNFalpha or chemo- or radio-therapies. From these studies as emerged the concept that NF-kappaB blockade could be associated to conventional therapies in order to increase their efficiency. This review focuses on the current knowledge on NF-kappaB regulation and discusses the therapeutic potential of targeting NF-kappaB in cancer in particular during radiotherapy.