The interaction between the recombinant human estrogen receptor and a variety of nonsteroidal estrogens was studied using a transient transfection assay in mammalian cells. Eight naturally occurring compounds were confirmed to stimulate the transcriptional activity of the human estrogen receptor and to compete for the binding of radiolabeled 17 beta-estradiol to this protein. In order of biological potency, these were zearalenone, beta-zearalenol, coumestrol, genistein, daidzein, phloretin, formononetin, and biochanin A. As with steroidal estrogens, the hormonal activity of these compounds was specific for the estrogen receptor and sensitive to inhibition by 4-hydroxytamoxifen and ICI-164,384. Evidence is also presented to indicate that the stimulatory activity of genistein is unrelated to the protein tyrosine kinase inhibitory activity of this isoflavone. These results demonstrate that a significant number of structurally diverse plant and fungal secondary metabolites exist in nature that may contribute to the total estrogen exposure of the human population.