Chemotherapy has been used to treat cancer for 60 years, despite an incomplete understanding of the mechanisms by which it is more toxic to cancer cells than normal cells. Now, Anthony Letai and colleagues show that a property called mitochondrial priming correlates with the clinical response to chemotherapy (Science, published online 27 October 2011; doi:10.1126/science.1206727). Chemotherapeutic drugs induce apoptosis or inactivate anti-apoptotic pathways. To measure a tumor cell's propensity to undergo mitochondrially mediated apoptosis, the authors exposed cells to BH3 peptides from pro-apoptotic proteins and monitored mitochondrial depolarization. The authors termed this property, which essentially measures the proximity of mitochondria to the apoptotic threshold, 'mitochondrial priming'. They then analyzed mitochondrial priming in 85 tumors before treatment. For each tumor type, the authors found evidence supporting a correlation between higher mitochondrial priming and a positive clinical response to chemotherapy. They tested whether modulating priming would alter chemosensitivity in vitro. Using ABT-737, a BH3-mimetic drug, to increase priming in a myeloid leukemia cell line, they observed an increase in sensitivity to three chemotherapeutic agents. The authors suggest that agents that selectively increase mitochondrial priming in cancer cells may enhance the clinical response to conventional chemotherapy.