The adenovirus E1A oncogene activates p53 through a signaling pathway involving the retinoblastoma protein and the tumor suppressor p19^ARF. The ability of E1A to induce p53 and its transcriptional targets is severely compromised in ARF-null cells, which remain resistant to apoptosis following serum depletion or adriamycin treatment. Reintroduction of p19^ARF restores p53 accumulation and resensitizes ARF-null cells to apoptotic signals. Therefore, p19^ARF functions as part of a p53-dependent failsafe mechanism to counter uncontrolled proliferation. Synergistic effects between the p19^ARF and DNA damage pathways in inducing p53 may contribute to E1A’s ability to enhance radio- and chemosensitivity.