Estrogen receptors (ER) have been targets of pharmacological intervention for decades. The use of menopausal hormone therapy (MHT) for improving cardiovascular health is associated with serious adverse effects and therefore cannot be recommended as a first-line strategy. While recently menopausal women in good cardiovascular health may be more likely to benefit from MHT than older women with worse risk profiles, adverse MHT effects such as increased risk for stroke have been consistently shown. Selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene have been developed to avoid such negative aspects of MHT. Based on available evidence, however, SERMs are not endowed with greater cardiovascular efficacy and safety than conventional MHT. By contrast, the newly developed SERM lasofoxifene has been shown to reduce cardiovascular events in post-menopausal women, although it also increased venous thromboembolic events in line with other ER-targeting agents. Fundamental research has shown that endothelial progenitor cells are important targets of estrogen actions in the cardiovascular system. This indicates that preferential targeting of specific cells and tissues is likely to enhance safety over nonselective hormone agents. Similarly, increased ER-isoform selectivity along with deeper understanding of ER biology should assist in designing novel ER modulators that are more effective and safer than currently used agents. In this article, we summarize the potential connections between SERMs and EPC biology, uncovering novel possible routes to cardiovascular risk reduction.