Chemotherapeutic agents simultaneously induce transcription factors p53 and NFκB. p53 induction can activate an apoptotic program, and resistance to chemotherapy correlates with the loss of a functional p53 pathway. By contrast, NFκB prevents apoptosis in response to chemotherapeutic agents. We have analyzed the p53 response in IKK1/2^−/− MEFs, which lack detectable NFκB activity. Compared to WT fibroblasts, IKK1/2^−/− fibroblasts showed increased cell death and p53 induction in response to the chemotherapeutic agent, doxorubicin. Reconstitution of IKK2, but not IKK1, increased Mdm2 levels and decreased doxorubicin-induced p53 stabilization and cell death. IKK2-mediated effects required its kinase function and were abrogated by coexpression of the dominant negative IκBαM, implying a role for NFκB in blocking chemotherapy-induced p53 and cell death.