We have developed a series of high-affinity peptide antagonists that inhibit the transcriptional activity of both subtypes of the human estrogen receptor (ERalpha and ERbeta). We believe that it will be possible to develop these peptides, or corresponding peptidomimetic derivatives, into pharmaceuticals for use in the treatment of breast cancer and other estrogenopathies. It is anticipated that drugs of this type could be used in combination with classical antiestrogens, such as tamoxifen, to achieve a complete blockage of ER-transcriptional activity. Although ER has been the primary target of our studies to date, it is likely that the insights gained from this work will apply to other nuclear receptors and transcription factors.