Acquired mutations can induce resistance to hormonal therapy in patients with breast cancer, suggest findings by Merenbakh-Lamin and colleagues. The investigators analysed samples obtained from 13 patients with metastatic breast cancer for mutations in cancer-related genes and identified a mutation in ERα in liver metastases of five patients who developed resistance to hormonal therapy. The primary tumours had not previously harboured this mutation, which structural modelling showed leads to a conformational change in the ligand-binding domain that ultimately alters binding of tamoxifen.