The biological effects of estrogen are mediated through estrogen receptors α and β (ERα, β). The classical mechanism of activation of ERs depends on ligand binding to the receptors, after which the receptors dimerize and bind to estrogen response elements (EREs) located in the promoters of estrogen-responsive genes. ERs may also regulate gene expression in the absence of DNA-binding by modulating the activities of other transcription factors via protein-protein interactions on DNA. This mechanism is referred to as cross-talk and is common for several nuclear receptors. As the name implies, the family of estrogen receptor-related receptors (ERRs) is a subfamily of the orphan nuclear receptors, which is closely related to the estrogen receptor (ER) family, and comprises three subtypes (ERRα-γ). Sequence analyses comparing all the class 3 NRs have shown that both ERs and ERRs together form the same branch of class 3, which recognizes a specific hormone response element (HRE), whereas the other four steroid receptors (PR, AR, GR, and MR) recognize a different, yet specific HRE, thereby forming another branch.