Extended exposure to the selective estrogen receptor modulators (SERMs) such as raloxifene to prevent osteoporosis and tamoxifen or the aromatase inhibitors to treat or prevent breast cancer are established therapeutic strategies. However, there are now clearly defined consequences of exhaustive antihormonal therapy in breast cancer. Ultimately, drug resistance to SERMs and aromatase inhibitors enhances cancer cell survival but a paradoxical supersensitivity to estrogen action develops that causes cancer cell apoptosis. The future exploitation of these novel data will allow selective killing of cancer with fewer side effects for patients.