determined. High levels of cellular proliferation correlate well with a high ERα:ERβ ratio, but repression of cellular proliferation correlates to ERβ being dominant over ERα. The ratio of ERs in neoplastic and normal breast tissue could be important when considering chemoprevention with SERMs. When looking at the differences between ERα and ERβ, Activating Function 1 (AF-1) and AF-2 are important. Together they play an important part in the interaction with other co-regulatory proteins that control gene transcription. AF-1 is located in the amino terminus of the ER and is only 20% homologous in ERα and ERβ. On the other hand, AF-2 is very similar in ERα and ERβ, and only one amino acid is different. Studies have shown that by switching AF-1 regions in ERα and ERβ, that there are specific differences in transcription activity. Generally, SERMs can partially activate engineered genes through ERα by an estrogen receptor element, but not through ERβ. Although, raloxifene and the active form of tamoxifen can stimulate AF-1-regulated reporter genes in both ERα and ERβ. Because of the discovery that there are two ER subtypes, it has brought about the synthesis of a range of receptor specific ligands that can switch on or off a particular receptor. However, the external shape of the resulting complex is what becomes the catalyst for changing the response at a tissue target to a SERM. X-ray crystallography of estrogens or antiestrogens has shown how ligands program the receptor complex to interact with other proteins. The ligand-binding domain of the ER demonstrates how ligands promote and prevent coactivator binding based on the shape of the estrogen or antiestrogen complex. The broad range of ligands that bind to the ER can create a spectrum of ER complexes that are fully estrogenic or antiestrogenic at a specific target site. The main result of a ligand-binding to ER is a structural rearrangement of the ligand-binding pocket, primarily in the AF-2 of the C-terminal region. The binding of ligands to ER leads to the formation of a hydrophobic pocket that regulates cofactors and receptor pharmacology. The correct folding of ligand-binding domain is required for activation of transcription and for ER to interact with a number of coactivators. Coactivators are not just protein partners that connect sites together in a complex. Coactivators play an active role in modifying the activity of a complex. Post-translation modification of coactivators can result in a dynamic model of