17β-Estradiol (E2) is a steroid hormone that regulates the expression of a variety of genes involved in distinct physiological processes, including development, metabolism, and reproduction. The effects start when the hormone binds to the specific intracellular receptors ERα and ERβ, which act via multiple mechanisms. E2 has profound, rapid effects on the conformation of ERs allowing receptor dimerization and translocation into the nucleus where they bind specific hormone response elements present in DNA. The ER-E2 complex can also function as a cytoplasmic signaling molecule eliciting other changes in cells, including modulation of ion fluxes across membranes and stimulation of kinase and phosphatase cascades which, in turn, may influence processes such as proliferation of various cell types. Such extranuclear signaling pathways are rapid and supposedly independent of transcription and require membrane localized ERs. The recent finding that ERs undergo palmitoylation provides new insights into E2 rapid signaling and raises several new concerns in the field of estrogen biology. S-palmitoylation allows ERα and ERβ localization at the plasma membrane, where they associate with caveolin-1. Upon E2 stimulation, ERα dissociates from caveolin-1, whereas ERβ:caveolin-1 association increases allowing the activation of specific rapid signals relevant for cell proliferation. Here recently disclosed information on membrane ERs, and the emerging field of membrane integration and nuclear receptor signaling will be highlighted.