Estrogens exert rapid, extranuclear effects by their action on the plasma membrane estrogen receptors (mERs). G alpha protein associated with the cell membrane is involved in many important processes regulated by estrogens. However, the G alpha's role in the mER-mediated signaling and the signaling pathways involved are poorly understood. This review aims to outline the G alpha's role in the mER-mediated signaling. Immunoblotting, immunofluorescence, co-immunoprecipitation, and RNA interference were carried out using vascular endothelial cells (ECs) and human breast carcinoma cell lines as experimental models. Electrophysiology and immunocytochemistry were carried out using guinea pigs as animal models. Recent advances suggest that the signaling of mER alpha through G alpha is required for vascular EC migration or endothelial H2S release, while G alpha(13) is involved in estrogen-induced breast cancer cell invasion. Besides, the G alpha(q)-coupled PLC-PKC-PKA pathway is critical for the neural regulation of energy homeostasis. This review summarizes the contributions of G alpha to mER-mediated signaling, including cardiovascular protection, breast cancer metastasis, neural regulation of homeostatic functions, and osteogenesis.