Estrogens importantly contribute to physiological homeostasis and exert their effects through genomic and non-genomic (“rapid”) actions [1, 2]. Rapid signaling of estrogen, which has been first reported in the 1960s [3-5] involves membrane estrogen receptors (ERs), including membrane subpopulations of ERalpha and ERbeta. In the early 1990s, rapid increases in cyclic AMP in response to estrogen were reported in human coronary arteries as well as in mammary and uterine cells [6, 7]. Shortly thereafter, several laboratories independently reported the cloning of an orphan G protein-coupled receptor from vascular and cancer cells that was named GPR30 [8-11]. Research published between 2000 and 2005 provided evidence that GPR30 binds and signals via estrogen indicating that this intracellular receptor is involved in rapid, non-genomic estrogen signaling [12-14]. The receptor has since been designated as the G protein-coupled estrogen receptor (GPER) by the International Union of Pharmacology [15]. The availability of genetic tools such as different lines of GPER knock-out mice, as well as GPER-selective agonists and antagonists has advanced our understanding, but also added some confusion about the new functions of this receptor (reviewed in [16]). Research of the past decade has provided evidence that GPER is critically involved in the regulation of vascular tone and blood pressure , metablic control [17], inflammation, and reproductive biology, among others. It is important to note that GPER not only binds estrogens but also other substances, including SERMs, SERDs, and environmental ER activators (endocrine disruptors; xenoestrogens) and also interacts with other proteins [18]. The current knowledge and unresolved questions about GPER-dependent signaling and function in health an disease will be discussed, as well as controversies that have complicated our understanding of GPER function, including interactions with human ERa-36 and aldosterone as a potential ligand [18]. 1 Mendelsohn ME, Karas RH: Molecular and cellular basis of cardiovascular gender differences. Science 2005;308:1583-1587. 2 Levin ER: Rapid signaling by steroid receptors. Am J Physiol Regul Integr Comp Physiol 2008;295:R1425-1430. 3 Szego CM, Davis JS: Adenosine 3′,5′-monophosphate in rat uterus: acute elevation by estrogen. Proc Natl Acad Sci U S A 1967;58:1711-1718. 4 Szego CM, Davis JS: Inhibition of estrogen-induced elevation of cyclic 3′,5′-adenosine monophosphate in rat uterus. I. By beta-adrenergic receptor-blocking drugs. Mol Pharmacol 1969;5:470-480. 5 Pietras RJ, Szego CM: Endometrial cell calcium and oestrogen action. Nature 1975;253:357-359. 6 Mugge A, Riedel M, Barton M, Kuhn M, Lichtlen PR: Endothelium independent relaxation of human coronary arteries by 17 beta-oestradiol in vitro. Cardiovasc Res 1993;27:1939-1942. 7 Aronica SM, Kraus WL, Katzenellenbogen BS: Estrogen action via the cAMP signaling pathway: stimulation of adenylate cyclase and cAMP-regulated gene transcription. Proc Natl Acad Sci U S A 1994;91:8517-8521. 8 Owman C, et al.: Cloning of human cDNA encoding a novel heptahelix receptor expressed in Burkitt’s lymphoma and widely distributed in brain and peripheral tissues. Biochem Biophys Res Commun 1996;228:285-292. 9 Carmeci C et al.: Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer. Genomics 1997;45:607-617. 10 Takada Y, et al.: Cloning of cDNAs encoding G protein-coupled receptor expressed in human endothelial cells exposed to fluid shear stress. Biochem Biophys Res Commun 1997;240:737-741. 11 O’Dowd BF, et al.: Discovery of three novel G-protein-coupled receptor genes. Genomics 1998;47:310-313. 12 Filardo EJ, Qet al.: Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol 2000;14:1649-1660. 13 Revankar CM, et al.: A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 2005;307:1625-1630. 14 Thomas P, Pang Y, Filardo EJ, Dong J: Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology 2005;146:624-632. 15 Alexander SP, Mathie A, Peters JA: Guide to Receptors and Channels (GRAC), 5th edition. Br J Pharmacol 2011;164 Suppl 1:S1-324. 16 Prossnitz ER, Barton M: The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol 2011;7:715-726. 17 Tiano JP, et al.: Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents beta cell failure in rodent models of type 2 diabetes. J Clin Invest 2011;121:3331-3342. 18 Barton M: Position paper: The membrane estrogen receptor GPER–Clues and questions. Steroids 2012;77:935-942.