New drugs that neutralize the antiapoptotic members of the Bcl-2 family hold promise for rational cancer therapies, both alone and in combination with other agents. An understanding of how and why such agents may trigger apoptosis on their own, and how resistance to these drugs can occur, depends on the complexity of the Bcl-2 family interactions that control mitochondrial outer membrane permeabilization (MOMP). By extracting mitochondria from tumor cells and exposing them to peptides corresponding to the regulatory BH3-only proteins, MOMP predicts not only which cells will undergo apoptosis in response to Bcl-2 antagonists, but also why other cells may be resistant.