Several recent studies of mouse models of cancer have provided direct genetic evidence for the critical role of NF-kappaB in carcinogenesis. While it has long been known that NF-kappaB is a key mediator of chemotherapy resistance, it is now clear that the transcription factor also has a major role in tumour development, particularly at its earlier phases. However, the role of NF-kappaB in tumourigenesis is more complex than anticipated, as in some models NF-kappaB inhibition blocks, whereas in others it facilitates, tumour development. In this paper we review current knowledge and suggest a general hypothesis that attempts to resolve this apparent paradox. Further cancer model studies should help to clarify this issue, complementing the intensive drug development effort of the pharmaceutical industry around NF-kappaB.