Decisions regarding the assignment of hormonal therapy for breast cancer are based solely upon the presence of nuclear estrogen receptors (ERs) in biopsied tumor tissue. This is despite the fact that the G-protein-coupled estrogen receptor (GPER) is linked to advanced breast cancer and is required for breast cancer stem cell survival, an observation that suggests that effective endocrine therapy should also target this receptor. Here, two ER/GPER-targeting proteolytic chimeras (UI-EP001 and UI-EP002) are described that effectively degrade ERα, ERβ, and GPER. These chimeras form high-affinity interactions with GPER and ER with binding dissociation constants of ∼30 nM and 10-20 nM, respectively. Plasma membrane and intracellular GPER and nuclear ER were degraded by UI-EP001 and UI-EP002, but not by a partial proteolytic targeting chimera (PROTAC) lacking its estrogen-targeting domain. Pretreatment of cells with the proteasomal inhibitor, MG132, blocked UI-EP001 and UI-EP002 proteolysis, while the lysosomotrophic inhibitor, chloroquine, had no effect. The off-target activity was not observed against recombinant β1-adrenergic receptor or CXCR4. Target specificity was further demonstrated in human MCF-7 cells where both drugs effectively degraded ERα, ERβ, and GPER, sparing the progesterone receptor (PR). UI-EP001 and UI-EP002 induced cytotoxicity and G2/M cell cycle arrest in MCF-7 breast cancer and human SKBR3 (ERα-ERβ-GPER+) breast cancer cells but not human MDA-MB-231 breast cancer cells that do not express functional GPER/ER. These results suggest that it is possible to develop a receptor-based strategy of antiestrogen treatment for breast cancer that targets both plasma membrane and intracellular estrogen receptors.