Endocrine therapies, first used more than 100 years ago, are the most effective treatments for breast cancers expressing the estrogen receptor (ER). All endocrine therapies are designed to block ER function in some way, thereby making them the first targeted therapies used for cancer. Selective ER modulators (SERMs) such as tamoxifen bind ER and partially block its activity. Ovarian ablation, luteinizing hormone–releasing hormone agonists, and aromatase inhibitors reduce the level of estrogen and inhibit ligand-induced activation of ER. Steroidal antiestrogens such as fulvestrant bind ER, more completely block its function, and induce receptor degradation. While all of these therapies are effective in certain patients, de novo and acquired resistance remain major problems. New information on the biology of ER provides insight into the mechanisms of treatment resistance and new strategies to overcome it, thereby potentially making these therapies even more effective.