Estrogens used in hormone replacement therapy regimens may increase the risk of developing breast cancer. Paradoxically, high consumption of plant-derived phytoestrogens, particularly soybean isoflavones, is associated with a low incidence of breast cancer. To explore the molecular basis for these potential different clinical outcomes, we investigated whether soybean isoflavones elicit distinct transcriptional actions from estrogens. Our results demonstrate that the estrogen 17beta-estradiol effectively triggers the transcriptional activation and repression pathways with both estrogen receptors (ERs) ERalpha and ERbeta. In contrast, soybean isoflavones (genistein, daidzein, and biochanin A) are ERbeta-selective agonists of transcriptional repression and activation at physiological levels. The molecular mechanism for ERbeta selectivity by isoflavones involves their capacity to create an activation function-2 surface of ERbeta that has a greater affinity for coregulators than ERalpha. Phytoestrogens may act as natural selective estrogen receptor modulators that elicit distinct clinical effects from estrogens used for hormone replacement by selectively recruiting coregulatory proteins to ERbeta that trigger transcriptional pathways.