The p53 transcription factor responds to a variety of intrinsic stresses, such as DNA damage, hypoxia, and even oncogene activation. NF-κB responds to a large number of extrinsic stresses such as cytokine activation and infectious diseases. The p53 tumor suppressor limits the consequences of stress by initiating cell death, senescence, or cell cycle arrest and promotes metabolic patterns in the cell to favor oxidative phosphorylation. NF-κB, the oncogene, promotes cell division, which initiates the innate and adaptive immune responses utilizing large amounts of glucose in aerobic glycolysis, resulting in the synthesis of substrates for cell division. Thus these two transcription factors, both of which have evolved to respond to different types of stress, have adopted opposite strategies and cannot function in the same cell at the same time. On activation of one of these transcription factors, the other is inactivated. This is achieved at several places in the p53 and NF-κB pathways where regulatory proteins act on both p53 and NF-κB with opposite functional consequences. These internodal sites create core regulatory circuits essential for integrating two central pathways in cells.