Recent years have witnessed an exponential increase in our knowledge about the cellular suicide programme of apoptosis. Historically, genetic screens in model organisms such as C.elegans and D. melanogaster were among the experiments that initiated this field. While mammalian cell culture systems did not seem to be amenable for screening, recent developments in high-throughput assays such as robotic instrumentation, the annotation of complete mammalian genomes and novel genetic tools such as RNA interference have led to a number of genetic screens in mammalian culture cells. Some of these screens were focussed on cell death and resulted in a considerable extension of our knowledge on apoptosis. Here we summarize the underlying concepts and the data that these genetic screens generated so far. The results indicate a complex range of signalling pathways in mammals. In particular, numerous signalling components in mitochondria have been discovered in this way in accordance with the prominent role of this organelle for cell death regulation.