An important new concept associated with estrogen receptor (ER) function in breast cancer is that ER status/ phenotype is multifaceted. In particular, the two full-length, ligand binding ERs (ER-alpha and ER-beta) and possibly multiple variant isoforms of ER must be considered. In addition, cross-talk factors that can influence ER activity in a ligand independent fashion and factors downstream of the ER, including coactivators and corepressors, clearly have important roles in ER function. Their careful evaluation in addition to ER status will be necessary to more fully understand the etiology of breast cancer and the changes occurring in estrogen signaling during breast tumorigenesis and breast cancer progression. Such knowledge is necessary to have a significant impact on better prevention and treatment strategies for human breast cancer.