Programmed cell death is used by multicellular organisms to eliminate excess, damaged or harmful cells. This process of cell suicide, defined in morphological terms as apoptosis, is crucial for developmental morphogenesis, tissue homeostasis and defense against pathogens. Over the past decade, our understanding of the genetic basis of the cell death machinery has grown exponentially using genetically modified organisms. In particular, inactivation of genes involved in cell death using homologous recombination in mice has provided an invaluable tool to understand the mechanisms, as well as the structural and functional consequences, of programmed cell death in mammals. This review discusses recent insights into the cellular death program as revealed by these mutant animals.