Oestrogen receptor (ER)-positive breast tumours, commonly treated with tamoxifen, often express high levels of the pro-survival protein BCL-2. Vaillant et al. found that treatment of ER+ patient-derived breast tumour xenografts with the BH3 mimetic ABT-737 or a BCL-2-selective inhibitor (ABT-199) improved the response to tamoxifen. Additional benefit was obtained by adding inhibitors of PI3K or mTOR, as the PI3K–mTOR pathway is commonly activated in breast cancer, to tumours that only partially responded to BH3 mimetics and tamoxifen. Interestingly, BH3 mimetics could also reduce endometrial hyperplasia, a common side effect of tamoxifen treatment. These results support the clinical evaluation of BH3 mimetics in ER+ breast cancer, and BCL-2 expression may provide a useful biomarker to predict efficacy.