Although the transcription factor NF-κB is most clearly linked to the inhibition of extrinsic apoptotic signals such as TNFα by upregulating known anti-apoptotic genes, NF-κB has also been proposed to be required for p53-induced apoptosis in transformed cells. However, the involvement of NF-κB in this process is poorly understood. Here we investigate this mechanism and show that in transformed MEFs lacking NF-κB (p65-null cells) genotoxin-induced cytochrome c release is compromised. To further address how NF-κB contributes to apoptosis, gene profiling by microarray analysis of MEFs was performed, revealing that NF-κB is required for expression of Noxa, a pro-apoptotic BH3-only protein that is induced by genotoxins and that triggers cytochrome c release. Moreover, we find that in the absence of NF-κB, genotoxin treatment cannot induce Noxa mRNA expression. Noxa expression had been shown to be regulated directly by genes of the p53 family, like p73 and p63, following genotoxin treatment. Here we show that p73 is activated after genotoxin treatment only in the presence of NF-κB and that p73 induces Noxa gene expression through the p53 element in the promoter. Together our data provides an explanation for how loss of NF-κB abrogates genotoxin-induced apoptosis.