SERM act on the estrogen receptor (ER), which is an intracellular, ligand-dependent transcriptional activator and belongs to the nuclear receptor family. Two different subtypes of ER have been identified, ERα and ERβ. ERα is considered the main medium where estrogen signals are transduced at the transcriptional level and is the predominant ER in the female reproductive tract and mammary glands while ERβ is primarily in vascular endothelial cells, bone, and male prostate tissue. ERα and ERβ concentration are known to be different in tissues during development, aging or disease state. Many characteristics are similar between these two types such as size (~600 and 530 amino acids) and structure. ERα and ERβ share approximately 97% of the amino-acid sequence identity in the DNA-binding domain and about 56% in the ligand-binding domain (see figure 3). The main difference of the ligand-binding domains is determined by Leu-384 and Met-421 in ERα, which are replaced by Met-336 and Ile-373, respectively, in ERβ. The variation is greater on the N-terminus between ERα and ERβ.