The measurement of estrogen receptor (ER)alpha in breast cancer tissues is important to discriminate between the hormone dependent and independent tumors. Recently, a second ER, referred to as ERbeta, has been identified. The DNA binding domain of ERbeta is 96% conserved compared with ERalpha, and the ligand binding domain shows 53% conserved residues, suggesting that both receptors can bind estrogen responsive elements on target genes, and that they may also bind similar ligand. While both receptors bind to 17beta-estradiol with equal affinity, other compounds bind with varying affinities to the two receptors. Since the function of ERbeta in breast cancer progression is not well understood, further characterization of the function of ERbeta and its isoforms in breast cancer is warranted. Various kinds of cofactors, such as steroid receptor coactivator-1 (SRC-1), transcription intermediary factor 2 (TIF2), and amplified in breast cancer 1 (AIB1), have also been reported. These coactivators interact with nuclear receptors in a ligand-dependent manner and enhance transcriptional activation by the receptor via histone acetylation/methylation and recruitment of additional coactivator, such as CREB binding protein (CBP)/p300. Thus, action of estrogen is not as simple as thought previously, and is likely influenced by ERbeta, its variants and interaction with cofactors. Improved understanding of the ER mechanism may follow from the discovery of these proteins, although their precise roles remain to be determined.