Estrogen-induced rapid, membrane-initiated activation of numerous signal transduction cascades has been shown in animal, cellular and molecular vascular studies, which support the favorable effects of estrogen on vascular structure and function. These effects are mediated by distinct forms of estrogen receptor (ER) alpha. This includes estrogen-stimulated, rapid activation of endothelial nitric oxide synthase (eNOS), resulting in elaboration of the athero-protective, angiogenesis-promoting product nitric oxide (NO). An N-terminus truncated short isoform of ERalpha, ER46, plays a critical role in membrane-initiated, rapid responses to 17beta-estradiol (E2) in human endothelial cells (ECs). We have proposed a ER46-centered, eNOS-activating molecular complex in human EC caveolar membranes, containing c-Src, phosphatidylinositol 3-kinase (PI3K), Akt and eNOS. In this review, we describe estrogen-induced, rapid, non-genomic actions in the endothelium.