17Beta-estradiol (E2) controls many aspects of human physiology, including development, reproduction and homeostasis, through regulation of the transcriptional activity of its cognate receptors (ERs). The crystal structures of ERs with agonists and antagonists and the use of transgenic animals have revealed much about how hormone binding influences ER conformation(s) and how this conformation(s), in turn, influences the interaction of ERs with co-activators or co-repressors and hence determines ER binding to DNA and cellular outcomes. This information has helped to shed light on the connection between E2 and the development or progression of numerous diseases. Current therapeutic strategy in the treatment of E2-related pathologies relies on the modulation of ER trancriptional activity by anti-estrogens; however, data accumulated during the last five years reveal that ER activities are not only restricted to the nucleus. ERs are very mobile proteins continuously shuttling between protein targets located within various cellular compartments (e.g., membrane, nucleus). This allows E2 to generate different and synergic signal transduction pathways (i.e., non-genomic and genomic) which provide plasticity for cell response to E2. Understanding the structural basis and the molecular mechanisms by which ER transduce E2 signals in target cells will allow to create new pharmacologic therapies aimed at the treatment of a variety of human diseases affecting the cardiovascular system, the reproductive system, the skeletal system, the nervous system, the mammary gland, and many others.