The tumor suppressor gene p53 regulates multiple cellular responses to DNA damage, but the transcriptional targets that specify these responses are incompletely understood. We describe a Drosophila p53 homolog and demonstrate that it can activate transcription from a promoter containing binding sites for human p53. Dominant-negative forms of Drosophila p53 inhibit both transactivation in cultured cells and radiation-induced apoptosis in developing tissues. The cis-regulatory region of the proapoptotic gene reaper contains a radiation-inducible enhancer that includes a consensus p53 binding site. Drosophila p53 can activate transcription from this site in yeast and a multimer of this site is sufficient for radiation induction in vivo. These results indicate that reaper is a direct transcriptional target of Drosophila p53 following DNA damage.