The temporal and tissue-specific actions of estrogen are mediated by estrogen receptors alpha and beta. The ERs are steroid hormone receptors that modulate the transcription of target genes when bound to ligand. The activity of these transcription factors is regulated by a variety of factors, including ligand binding, phosphorylation, coregulators, and the effector pathway (ERE, AP1, SP1). The end result of target gene transcription is to modulate physiological processes, such as reproductive organ development and function, bone density, and unfortunately contribute to the growth and development of breast and endometrial cancer. The complex biological effects mediated by ER alpha and ER beta involve communication between many proteins and signaling pathways. An ultimate goal of current research is to enhance the value of the separate estrogen receptors as targets for therapeutic intervention.