A cell’s sensitivity to apoptotic stimuli is highly variable, making it possible for the same stimuli to trigger a death response in one tissue and not in another. Previous research in our lab has shown that differences in sensitivity to apoptotic stimuli during Drosophila development are established by regulating levels of pro-apoptotic proteins—cells with lower levels being less sensitive to apoptotic stimuli. We hypothesized that histone deacetylases (HDACs) could play a major role in repressing transcription of pro-apoptotic genes in tissues with low sensitivity. By using HDAC inhibitory drugs, we showed that reducing the activity of Class I HDACs is sufficient to increase expression of pro-apoptotic genes and thereby elevate apoptotic sensitivity. We then used knockdown of individual HDACs to identify Rpd3 as the HDAC most responsible for these changes in responsiveness to apoptotic stimuli in whole animals as well as in specific tissues. HDAC inhibitors are used widely in drug cocktails to treat cancer patients, but the mechanism by which they act is not wholly clarified. Our results suggest that these drugs may act, at least in part, by priming both normal and malignant cells for a death response.