The estrogen receptor (ER), a member of the nuclear hormone receptor superfamily, is a hormone-regulated transcription factor that mediates the effects of estrogens and antiestrogens in breast cancer and other estrogen target cells. Because of the role of estrogens in promoting the growth and progression of breast cancer, there is great interest in exploring ways to functionally inactivate the ER, thereby suppressing ER-mediated gene expression and cell proliferation. These approaches have involved the use of antiestrogens such as tamoxifen, dominant negative ERs and, more recently, the use of corepressors. Through the use of two-hybrid screening, we have recently identified a selective repressor of estrogen receptor activity (REA). This protein is recruited to the hormone-occupied ER and selectively represses its transcriptional activity but not the other steroid and non-steroid nuclear receptors. REA also interacts with a protein, prothymosin-alpha (PTalpha), that selectively enhances ER transcriptional activity by recruiting the repressive REA protein away from ER. Analysis of the mechanisms underlying the activities of these two proteins highlights a new role for REA and PTalpha as activity-modulating proteins that confer receptor specificity.