As an agonist of the classical nuclear receptors, estrogen receptor-α and -β (NR3A1/2), estrogen has been assumed to inhibit the development of cardiovascular disease in premenopausal women. Indeed, reduced levels of estrogen after menopause are believed to contribute to accelerated morbidity and mortality rates in women. However, estrogen replacement therapy has variable effects on cardiovascular risk in postmenopausal women, including increased serious adverse events. Interestingly, preclinical studies have shown that selective activation of the novel membrane-associated G protein-coupled estrogen receptor, GPER, can promote cardiovascular protection. These benefits are more evident in ovariectomised than intact females or in males. It is therefore possible that selective targeting of the GPER in postmenopausal women could provide cardiovascular protection with fewer adverse effects that are caused by conventional 'receptor non-specific' estrogen replacement therapy. This review describes new data regarding the merits of targeting GPER to treat cardiovascular disease with a focus on sex differences. © 2021 The British Pharmacological Society.