Alterations in MYC and p53 are hallmarks of cancer. p53 coordinates the response to gamma irradiation (γ-IR) by either triggering apoptosis or cell cycle arrest. c-Myc activates the p53 apoptotic checkpoint, and thus tumors overexpressing MYC often harbor p53 mutations. Nonetheless, many of these cancers are responsive to therapy, suggesting that Myc may sensitize cells to γ-IR independent of p53. In mouse embryo fibroblasts (MEFs) and in Eμ-myc transgenic B cells in vivo, c-Myc acts in synergy with γ-IR to trigger apoptosis, but alone, when cultured in growth medium, it does not induce a DNA damage response. Surprisingly, c-Myc also sensitizes p53-deficient MEFs to γ-IR-induced apoptosis. In normal cells, and in precancerous B cells of Eμ-myc transgenic mice, this apoptotic response is associated with the suppression of the antiapoptotic regulators Bcl-2 and Bcl-XL and with the concomitant induction of Puma, a proapoptotic BH3-only protein. However, in p53-null MEFs only Bcl-XL expression was suppressed, suggesting levels of Bcl-XL regulate the response to γ-IR. Indeed, Bcl-XL overexpression blocked this apoptotic response, whereas bcl-X-deficient MEFs were inherently and selectively sensitive to γ-IR-induced apoptosis. Therefore, MYC may sensitize tumor cells to DNA damage by suppressing Bcl-X.