Estrogen receptor alpha (ER) plays a key role in the development and progression of breast cancer as well as the treatment and outcome of breast cancer patients. In normal mammary epithelial cells, the level of ER fluctuates during the menstrual cycle in response to cyclical changes in estrogen. However, in breast cancer normal control of ER gene expression and/or function is lost. Of particular interest, the absence of ER in mammary carcinomas is associated with a less-differentiated phenotype and resistance to endocrine therapies. This review focuses on our current understanding of the mechanisms that regulate ER alpha gene expression and function in breast cancer. These include alteration of the ER gene, loss of gene expression, alternative splicing of ER RNA, posttranslational modification of the protein, and interaction of ER with other proteins that can modify its function.