The estrogen receptor (ER) binds to estrogen responsive elements (EREs) to activate gene transcription. The best characterized EREs are located in proximal gene promoters, but recent data indicate that only a minority of ER binding sites lie within proximal promoter regions. GREB1 (gene regulated by estrogen in breast cancer 1) is an ER target gene that regulates estrogen-induced proliferation in breast cancer cells. We identified three consensus EREs, located at -21.2 kb, -9.5 kb and -1.6 kb upstream of the closest GREB1a transcription start site that appear to mediate long-range GREB1 gene activation by ER. All three ERE sites nucleate ER, SRC-3, Pol II and undergo histone acetylation in response to estradiol. Estrogen stimulated ER binding at all three EREs was cyclic and synchronous. SRC-3 and Pol II recruitment to all three EREs was activated by estrogen, but not tamoxifen. In contrast, estrogen stimulated only Pol II, and not ER or SRC-3 recruitment to the GREB1 core promoter regions. Long-range histone acetylation, centered on the three ERE motifs and the GREB1 core promoters, was observed in response to estrogen, but not to tamoxifen. These data suggest that estrogen stimulated GREB1 transcription may involve coordinated ER binding to all three distal consensus ERE motifs. Long-range activation by ER acting at multiple EREs may be more common than previously appreciated.