Estrogen induces the binding of ERa to thousands of locations in the breast cancer genome, preferring intergenic and distal regions rather than near the promoters of estrogen-regulated genes. With recent technological innovations in mapping and characterization of global chromatin organization, evidence now indicates ERa mediates long-range chromatin interactions to control gene transcription. The principles that govern how ERa communicates with their putative target genes via chromosomal interactions are also beginning to unravel. Herein, we summarize our current knowledge on the functional signifi- cance of chromatin looping in estrogen-mediated transcription. ERa collaborative factors and other players that contribute to define the genomic interactions in breast cancer cells will also be discussed. Defects in chromatin organization are emerging key players in diseases such as cancer, thus understanding how ERa-mediated chromatin looping affects genome organization will clarify the receptor’s role in estrogen responsive pathways sensitive to defects in chromatin organization.