The role of estrogens in breast and other cancers has been extensively investigated for many years, and historically most of these studies have focused on the hormonal regulation of cell proliferation. The most recent work in this area has focused on the expression of genes likely to mediate proliferation (e.g., growth factors, proto-oncogenes, etc.) and their regulation by the classic nuclear estrogen receptor, ER-alpha. In this chapter, we present a synopsis of several new developments in this area of ER-regulated gene expression. These developments include the following: 1) the selective activation of ER domains by partial estrogen antagonists, such as tamoxifen and other ligands; 2) the effects of ER-alpha overexpression and gene knockout on the development of breast and uterine cancers in experimental animal models; 3) mechanisms by which steroid hormones regulate programmed cell death, cell cycle progression, cell-substratum interactions, and genomic instability in cancer cells; 4) identification of nuclear proteins that interact with the ER in the presence of agonists and antagonists, the effect of ligand binding on the receptor structure, and the interactions of liganded and nonliganded receptors with coactivators, corepressors, and other regulatory proteins; and 5) the biochemical properties, cellular distribution, and potential biologic roles for the newly discovered ER-beta. Although there is an increasing interest in understanding the role of estrogens as endogenous carcinogens, it remains clear that ER-mediated regulation of gene expression plays many significant roles in normal and cancer cells, and increased knowledge of the mechanisms involved will improve our overall understanding of hormonal carcinogenesis.