For more than 50 years, estrogen receptor alpha (ER) has been widely used as a predictive and prognostic biomarker in breast cancer. ER is also a well-established therapeutic target and numerous drugs have been developed that target ER, both indirectly (AIs, aromatase inhibitors) and directly as tissue-selective ER inhibitors, falling in to two general categories: SERMs (selective ER modulators) or SERDs (selective ER degraders). A major unresolved clinical issue is the development of endocrine therapy (ET) resistance, which invariably occurs during prolonged adjuvant ET. A significant contributing mechanism by which tumors progress is through the acquisition of activating mutations in the ESR1 gene, most notably in the ER ligand-binding domain. We, and others, have observed somatic ESR1 mutations in up to 40% of metastatic tumors obtained from women who have acquired resistance to various endocrine therapies, especially to AIs. The two most common mutations are Y537S and D538G, both of which stabilize and/or facilitate the formation of an active AF-2 conformation in the ER LBD. A combination of structural, biophysical, cell and animal studies have helped define the underlying molecular mechanisms that account for AI/SERM/SERD resistance related to ESR1 mutations, which has contributed to the development of next generation SERMs and SERDs with potential improved clinical utility. Several of these drugs are currently being tested in clinical trials.