The steroid hormone estrogen has potent effects in a variety of tissues across the body in both females and males. In the nuclear signaling pathway for estrogens, the hormone acts by stimulating the DNA binding and transcriptional activity of estrogen receptors (ERs), transcription factors which robustly and transiently regulate the expression of target genes. More broadly, estrogen signaling controls the ER cistrome, as well as the epigenome and the estrogen-regulated transcriptome. A host of deep sequencing-based genomic assays have provided novel insights into the mechanisms by which ERs regulate transcriptional responses. Estrogen-dependent transcriptional responses have been studied widely in breast cancer cells, primarily in the context of the ER alpha (ERα) isoform. These studies have revealed an intricate cross talk between the estrogen-ERα signaling pathway and other signaling pathways, impacting transcriptional programs and clinical outcomes in breast cancer. This chapter reviews the key features of ERα-regulated transcription and the current technological advances that have allowed for the careful dissection of these mechanisms.