Abstract: Estrogen receptor α36 (ERα36), a splice variant of ERα66, is crucial in the pathogenesis, progression, and therapeutic resistance of female estrogen-related tumors (e.g., breast, cervical, and endometrial cancers) as it uniquely activates non-genomic signaling pathways. This review provides a comprehensive summary of the structural features of ERα36 and its molecular mechanisms in regulating tumor proliferation, migration, and drug resistance via membrane-mediated pathways, including phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). The interaction between ERα36 and epidermal growth factor receptor/human epidermal growth factor receptor2 (EGFR/HER2) forms a positive feedback loop that exacerbates malignant transformation. High ERα36 expression is associated with decreased sensitivity to chemotherapy and resistance to tamoxifen. Recent studies have demonstrated that natural compounds and synthetic inhibitors targeting ERα36 can reverse drug resistance and suppress cancer stem cell activity by blocking non-genomic signaling. This review provides novel insights into overcoming drug resistance and optimizing targeted therapies for female estrogen-related malignancies.