Novel estrogenic therapies are needed that ameliorate menopausal symptoms and have the bone-sparing effects of endogenous estrogens, but do not promote breast or uterine cancer. Recent evidence suggests that selective activation of the estrogen receptor subtype inhibits breast cancer cell proliferation. To establish whether ER-selective ligands represent a viable approach to improve hormone therapy, we investigated whether the estrogenic activities present in an herbal extract, MF101, used to treat hot flashes, are ER-selective. MF101 promoted ER, but not ER, activation of an estrogen response element (ERE) upstream of the luciferase reporter gene. MF101 also selectively regulates transcription of endogenous genes through ER. The ER-selectivity was not due to differential binding, since MF101 binds equally to ER and ER. Fluorescence resonance energy transfer and protease digestion studies showed that MF101 produces a different conformation in ER from ER, when compared with the conformations produced by estradiol. The specific conformational change induced by MF101 allows ER to bind to an ERE and recruit coregulatory proteins that are required for gene activation. MF101 did not activate the ER-regulated proliferative genes, c-myc and cyclin D1, or stimulate MCF-7 breast cancer cell proliferation or tumor formation in a mouse xenograft model. Our results demonstrate that herbal ER-selective estrogens may be a safer alternative for hormone therapy to estrogens that non-selectively activate both ER subtypes.