Estrogen and its receptors alpha and beta (ERalpha and ERbeta) play a major role in tumor progression and approximately two-thirds of breast cancers express these functional receptors. Thus, the ER is a major target for current and developing therapies. Although most ER-positive tumors initially respond to hormonal therapies such as tamoxifen, many tumors will eventually become resistant to tamoxifen induced growth inhibition. This chapter will discuss molecular mechanisms that contribute to hormonal resistance of current therapies including ERalpha mutations, the roles of proliferation and apoptosis in tumor homeostasis and receptor coregulator proteins. Additionally, the role of nonclassical ERalpha signaling through growth factor receptors and the subsequent downstream-initiated signaling, and the role of the progesterone receptors will be discussed.