Classically ER function in the nucleus as transcription factors mediating gene expression. We previously discovered that a subpopulation of ER are associated with the plasma membrane where they invoke robust beneficial responses to estrogen in endothelial cells and other cell types. These include the promotion of intimal layer integrity. The molecular basis of novel G protein coupling of membrane ER and the downstream targets modifying endothelial cell phenotype are being determined. In addition, novel ER ligands are being employed in vivo in mice to segregate membrane-initiated from classical ER actions in the vasculature, and also in the reproductive system and in breast cancer. Furthermore genetic strategies are being employed to segregate non-nuclear from nuclear ER actions both in cell culture and in vivo in mice. The ultimate goal is to determine if membrane-initiated ER actions can be selectively harnessed to provide cardiovascular protection without adverse effects on reproductive health or cancer risk.