The nuclear factor‐κB (NF‐κB) transcription factor family has been considered the central mediator of the inflammatory process and a key participant in innate and adaptive immune responses. Coincident with the molecular cloning of NF‐κB/RelA and identification of its kinship to the v‐Rel oncogene, it was anticipated that NF‐κB itself would be involved in cancer development. Oncogenic activating mutations in NF‐κB genes are rare and have been identified only in some lymphoid malignancies, while most NF‐κB activating mutations in lymphoid malignancies occur in upstream signaling components that feed into NF‐κB. NF‐κB activation is also prevalent in carcinomas, in which NF‐κB activation is mainly driven by inflammatory cytokines within the tumor microenvironment. Importantly, however, in all malignancies, NF‐κB acts in a cell type‐specific manner: activating survival genes within cancer cells and inflammation‐promoting genes in components of the tumor microenvironment. Yet, the complex biological functions of NF‐κB have made its therapeutic targeting a challenge.