Women live almost a third of their lives in a postmenopausal, estrogen-deficient state. Menopause is associated with increased in cardiovascular disease, adverse tissue remodeling, and cognitive decline in addition to other quality of life issues. However, currently prescribed menopausal hormone therapy is not clinically recommended for long-term treatment. Our goal is to elucidate estrogen receptor pharmacology to allow the development of pharmaceuticals that can selectively elicit cardiovascular protection in the absence of adverse effects. We focus our efforts on the G protein-coupled estrogen receptor (GPER), a unique membrane-bound hormone receptor that activates acute intracellular signaling, distinguishing it from the nuclear estrogen receptors ERα and ERβ. This receptor does not impact the reproductive actions of estrogen, indicating a unique receptor profile and a good target for eliciting estrogen’s cardiovascular benefits. We hope that our work will promote the improvement of menopausal hormonal therapies and therefore quality of life in aging women.