BH3-only proteins are the sentinels of cellular stress, and their activation commits cells to apoptosis. Since the discovery of the first BH3-only protein BAD almost 20 years ago, at least seven more BH3-only proteins have been identified in mammals. They are regulated by a variety of environmental stimuli or by developmental cues, and play a crucial role in cellular homeostasis. Some are considered to be tumor suppressors, and also play a significant role in other pathologies. Their non-apoptotic functions are controversial, but there is broad consensus emerging regarding their role in apoptosis, which may help in designing better therapeutic agents for treating a variety of human diseases.