This article reviews historical studies and recent advances regarding the direct effects of estrogen on the blood vessel wall. It is organized into two sections that summarize effects of estrogen on vasomotor tone and on vascular cell growth and atherogenesis, based on two recognized actions of estrogen on the vasculature: a rapid vasodilatory effect, and an atheroprotective effect involving inhibition of smooth-muscle cell proliferation. These effects are likely mediated by different mechanisms. The rapid vasodilatory effects of estrogen are probably nongenomic, whereas the antiproliferative effects of estrogen are likely due to estrogen receptor-dependent alterations in gene expression. Overlap between these two mechanisms also exists, in that genes regulating the production of two important vasodilators synthesized by the vessel wall (prostacyclin and nitric oxide) can be up-regulated by estrogen. Potential molecular mechanisms by which estrogen exerts its effects are discussed, and future directions in this rapidly evolving area of research are considered.