The nuclear factor κB (NF-κB) family is an evolutionarily conserved family of transcription factors that play a central role in immune and inflammatory responses. They also play a pivotal role in cell survival, whereby activation of NF-κB antagonizes programmed cell death induced by tumor necrosis factor receptors and other cell death signals. The prosurvival function of NF-κB has been implicated in a wide range of biological processes, including the development and homeostasis of the immune system and liver. It has also been implicated in the pathogenesis of numerous diseases, including cancer, chronic inflammation, and certain hereditary disorders. The protective activity of NF-κB can also hamper tumor cell killing inflicted by radiation or chemotherapeutic drugs, thereby promoting resistance to cancer treatments. This prosurvival activity of NF-κB involves the suppression of sustained c-Jun N-terminal kinase (JNK) activation and of the accumulation of cytotoxic reactive oxygen species. NF-κB mediates this function by inducing the transcription of target genes, whose products inhibit the JNK signaling pathway and suppress accumulation of reactive oxygen species through their antioxidant functions. The development of specific inhibitors that target the critical downstream NF-κB-regulated genes that promote survival in cancer and other diseases potentially holds a key to developing specific and effective therapeutic strategies to combat these disorders.