Estrogens demonstrate vasoprotective activity in many experimental models. These effects have been attributed to beneficial activity of these steroids on lipid metabolism as well as direct effects on the vasculature via modulation of nitric-oxide synthase and phosphatidylinositol-3 kinase/Akt signaling pathways. In this issue of Molecular Pharmacology, Stirone et al. (p. 959) present evidence suggesting that 17beta-estradiol may also exert vasoprotective effects in cerebral blood vessels via stimulation of mitochondrial energy production capacity and inhibition of reactive oxygen species production. These data indicate not only yet another potential mechanism underlying the vasoprotective effects of estrogens but also that the estrogen receptor may coordinate gene expression in both the nuclear and mitochondrial genomes.