During Drosophila development, large numbers of cells undergo natural cell death. Even though the onset of these deaths is controlled by many different signals, most of the dying cells undergo common morphological and biochemical changes that are characteristic of apoptosis in vertebrates. We have surveyed a large fraction of the Drosophila genome for genes that are required for programmed cell death by examining the pattern of apoptosis in embryos homozygous for previously identified chromosomal deletions. A single region on the third chromosome (in position 75Cl,2) was found to be essential for all cell deaths that normally occur during Drosophila embryogenesis. We have cloned the corresponding genomic DNA and isolated a gene, reaper, which is capable of restoring apoptosis when reintroduced into cell death defective deletions. The reaper gene is specifically expressed in cells that are doomed to die, and its expression precedes the first morphological signs of apoptosis by 1-2 h. This gene is also rapidly induced upon X-ray irradiation, and reaper deletions offer significant protection against radiation-induced apoptosis. Our results suggest that reaper represents a key regulatory switch for the activation of apoptosis in response to a variety of distinct signals.