The discovery of the estrogen receptor 60 years ago radically transformed the field of hormonal signaling and led to the recognition of ER as a prototype nuclear receptor that primarily functions as a transcription factor. In this chapter, we will first describe the conserved domain architecture of ER and its regulation through various modifications by diverse intracellular pathways. We will then discuss the history and most recent advancement in the understanding of ER regulation of target genes at both individual gene and whole genome levels. A number of new concepts emanated from these studies, including ER cistrome, pioneer factors, chromosome looping and enhancer RNA, etc. and their potential impact on the fight against breast cancer therapeutic resistance all will be discussed in detail in this chapter.