The estrogen-related-receptor-alpha (ERR alpha) is a nuclear hormone receptor identified by a lowstringency screen of a cDNA library with the estrogen-receptor-alpha (ER alpha) DNA binding domain and ERR alpha shares 60% sequence identity with ER alpha. ERR alpha is one of three estrogenrelated-receptors (ERRs). Despite sequence identity in the DNA-binding domain the ligand binding domains of ERR alpha and ER alpha are not as similar, such that ERR alpha does not bind estradiol. ERR alpha binds as a homodimer to the estrogen response element (ERE) and SF1 DNA sequences. No endogenous agonist for ERR alpha has been identified, but ERR alpha transcriptional activation occurs independent of ligand binding. The amino acid, Phe-232, is important to ERR alpha constitutive activity, such that a F232A mutation results in a loss of constitutive activity and the creation of a dominant negative mutant. Despite the absence of ligand binding ERR alpah has been shown to interact with the transcriptional co-activators PGC-1a and GRIP1. ERR alpha is expressed in many tissues including: heart, skeletal muscle, heart, kidney, liver and adipose tissue. ERR alpha -/- mice are resistant to high-fat diet induced obesity along with reduced lipogenesis in adipose tissue resulting in a lean phenotype, indicating a potential role in regulating metabolic homeostasis. ERR alpha has recently been shown to be an unfavorable biomarker for breast tumors due to its ability to activate estrogen-responsive genes in the absence of estrogen. There have been no endogenous ligands identified for ERR alpha. Two organochlorine pesticides (toxaphene and chlordane) have been shown to decrease ERR alpha constitutive activity. These compounds may disrupt the interaction of ERR alpha with its coactivators in the micromolar range but were toxic to cells at concentrations greater than 10 μM. A recently identified compound, XCT790, has been shown to act as an inverse agonist for ERR alpha. XCT790 disrupts the binding of GRIP1 and PGC-1a transcriptional co-activators to ERR alpha. The treatment of ERR alpha F232A mutants with XCT790 resulted in XCT790 functioning as an agonist increasing ERR alpha interaction with transcriptional co-activators.