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ER\u2010positive breast cancer, driven by estrogen signaling, is the most prevalent subtype worldwide. SERMs remain essential therapeutics, antagonizing estrogen activity in breast tissue while retaining agonist effects in bone and CVS. While traditional reviews have focused on triphenylethylene and benzothiophene scaffolds, this review provides a novel, insightful comprehensive analysis of emerging heterocyclic SERMS\u2014including indole, benzimidazole, coumarin, benzopyran, organometallic, and phytoestrogen derivatives\u2014linking chemical diversity with tissue\u2010selective mechanisms and structure\u2013activity relationships. Major limitations include incomplete receptor subtype selectivity, metabolic instability, partial agonism in nontarget tissues, and acquired endocrine resistance driven by ER mutations and growth factor signaling. This work uniquely integrates structural, mechanistic, and therapeutic insights and highlights innovative strategies, including dual SERM\u2010SERD scaffolds, combination with aromatase inhibitors, and computationally guided subtype\u2010selective design to overcome resistance, improve potency, and optimize clinical outcomes in ER\u2010positive breast cancer therapy.<\/jats:p>","DOI":"10.1002\/ardp.70206","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T10:57:18Z","timestamp":1771325838000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Selective Estrogen Receptor Modulators (SERMs): Advances, Challenges, and Future Prospects in ER+ Breast Cancer Therapy"],"prefix":"10.1002","volume":"359","author":[{"given":"Anurag","family":"Saini","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry National Institute of Pharmaceutical Education and Research Guwahati 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