In addition to nuclear-initiated (genomic) responses, estrogen receptors (ERs) have the ability to facilitate rapid, membrane-initiated, estrogen-triggered signaling cascades via a plasma membrane-associated form of the receptor. These rapid responses are dependent on assembly of membrane ER-centered multimolecular complexes, which can transduce ligand-activated signals to affect a variety of enzymatic pathways, often occurring in a cell-type-specific fashion with tissue-specific physiological outcomes. In some instances, cross-talk occurs between these membrane-initiated and nuclear responses, ultimately regulating transcriptional activation. The role of splice variants in membrane-initiated estrogen responses has been described, notably those within the vascular endothelium. In this review, we describe the evidence for membrane ERs, the molecular components of the aforementioned signaling complexes and pathways, the relevance of ER splice variants, and ER-mediated responses in specific tissues. Our growing understanding of ER-mediated actions at a molecular level will provide insight into the controversies surrounding hormone replacement therapy in postmenopausal women.