NF-κB in the crosshairs: Rethinking an old riddle.

•NF-κB transcription factors are central coordinating regulators of immunity, inflammation and cell survival.•NF-κB pathway is aberrantly and stably activated in cancer.•The ubiquitous presence and pleiotropic physiological role of NF-κB dimers have thus far prevented the development of any clinically useful NF-κB inhibitor.•Emerging therapeutic approaches aim to achieve the cancer-selective inhibition of the NF-κB pathway as a way to overcome the preclusive toxicities of conventional IKKβ/NF-κB-targeting drugs.