Programmed cell death (apoptosis) serves to remove excess, damaged, or infected cells throughout the lifespan of an organism. This process is critical for development of all metazoans, and its dysregulation can elicit morphogenetic abnormalities and disease. Many components of the cell death machinery have been identified in the past 15 years and their evolutionary conservation recognized through genetic and biochemical experiments in mammals, C. elegans, and D. melanogaster. These studies have led to our current understanding of the molecular mechanisms that control cell death. BH3-only proteins (members of the Bcl-2 family that have only one of the B cl-2 h omology regions, BH3) have recently been recognized as essential initiators of apoptosis, and this minireview focuses on their function.