Studies in bone, as well as other nonreproductive target tissues of sex steroid, like the cardiovascular and the central nervous system (CNS), have elucidated a previously unappreciated mechanism of sex steroid action involving the rapid activation of mitogen-activated protein kinases and/or phosphatidyl inositol 3 kinase, and consequent potent regulatory affects on the transcription of a set of genes that is distinct from that regulated through classic (genotropic) control of transcription. These actions stem from an unexpected function of the classic nuclear receptors outside the nucleus, most probably from receptor interactions within distinct signal transduction pathways in preassembled scaffolds. Importantly, these nongenotropic actions are mediated by the ligand-binding domain of the receptor and can be functionally dissociated from classic transcriptional activation with synthetic ligands, termed activators of nongenotropic estrogen-like signaling (ANGELS). We highlight this evidence and discuss its pharmacotherapeutic implications vis a vis the dilemmas posed by the recently appreciated shortfalls of postmenopausal hormone replacement therapy.