The Estrogen Receptor stands as one of the most successfully prosecuted drug targets in oncology, with the approval of the first ER-targeted therapies in the 1970s, and continued advancement of drugs through the 90s. The more recent discovery of highly prevalent ER mutations as a mechanism of resistance to standard-of-care endocrine therapies pointed to the continued dependence of tumors on ER, and led to a remarkable re-energizing of the field. Re-engagement of the pharmaceutical and biotechnology industries with ER as a drug target has been further underpinned by the impressive advances made in medicinal chemistry, enabling desirable mechanistic features to be combined with improved drug-like properties. We believe that by pursuing a deep understanding of our therapeutic candidates and their targets at the molecular, cellular, tissue and patient level, we will be best enabled to bring meaningful benefit to women with ER+ breast cancer. I will share some of our recent learnings on this front.