Estrogen Receptor (ER) is a nuclear receptor that mediates the actions of estrogen and tamoxifen. ER is expressed in a major fraction of human breast cancers. Recently, genomic maps for estrogen- and tamoxifen-ER have been published. Interestingly, estrogen and tamoxifen induce similar genomic interactions and both ligands have been shown to use co-operating factors. The interactions of these co-operating factors within ER regions have impact both on ER-DNA interactions and gene expression regulated by estrogen and tamoxifen. Moreover, the study of chromatin changes induced by these factors has also provided significant insight into our understanding of ER transcriptional regulation. This methods review describes some functional genomic methods to study the influence of both ER ligands and ER co-operating factors. The analysis of protein-DNA interactions and chromatin changes can be explored by using classical and novel methods such as Chromatin Immunoprecipitation (ChIP) or Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE). This review also explores the properties of each of these methods and the advantages of combining them with high throughput sequencing.