This study investigates the role of *ESR1* ligand binding domain (LBD) mutations in hormone-resistant breast cancer. The authors identified recurrent mutations in the LBD of *ESR1* in approximately 20% of metastatic ER+ breast cancer cases, specifically p.Tyr537Ser/Asn and p.Asp538Gly. These mutations were found in patients who had received hormonal therapy for an average of 4.9 years and were associated with hormone-resistant disease. Biochemical and structural analyses showed that these mutations promote the agonist conformation of the estrogen receptor (ER) in the absence of ligand, leading to increased ER activity and resistance to hormonal therapy. Functional studies in cell lines and animal models confirmed that these mutants can drive tumor growth in the absence of hormone. The findings suggest that more potent or selective ER antagonists may be beneficial for treating patients with these mutations.This study investigates the role of *ESR1* ligand binding domain (LBD) mutations in hormone-resistant breast cancer. The authors identified recurrent mutations in the LBD of *ESR1* in approximately 20% of metastatic ER+ breast cancer cases, specifically p.Tyr537Ser/Asn and p.Asp538Gly. These mutations were found in patients who had received hormonal therapy for an average of 4.9 years and were associated with hormone-resistant disease. Biochemical and structural analyses showed that these mutations promote the agonist conformation of the estrogen receptor (ER) in the absence of ligand, leading to increased ER activity and resistance to hormonal therapy. Functional studies in cell lines and animal models confirmed that these mutants can drive tumor growth in the absence of hormone. The findings suggest that more potent or selective ER antagonists may be beneficial for treating patients with these mutations.