B-cell lymphoma-2 (Bcl-2) homology-3 (BH3)-only proteins are considered members of the Bcl-2 family, though they bear little sequence or structural identity with the multi-BH motif prosurvival or proapoptotic Bcl-2 proteins like Bcl-2 or Bax. They are better considered a separate phylogenetic entity. In combination, results from biophysical, biochemical, cell biological, and animal studies in conjunction with structural investigations have elucidated the function and mechanism of action of these proteins. Either by antagonizing prosurvival Bcl-2 proteins or directly activating proapoptotic Bcl-2 proteins (Bax or Bak) they initiate apoptosis. BH3-only proteins are intrinsically disordered and fold and bind into a groove provided by their cognate receptor Bcl-2 family proteins. Our detailed molecular understanding of BH3-only protein action has aided the development of novel chemical entities that initiate cell death by mimicking the properties of BH3-only proteins.