Sex steroid receptors exist and function in pools localized to the plasma membrane, cytoplasm (mitochondria and endoplasmic reticulum), and the nucleus. Distinct actions of sex steroid hormones (such as estrogen) occur at each receptor pool and contribute to the integrated effects of these receptors for cellular functions. Sex steroid receptors traffic to the cell membrane through palmitoylation of a cystine residue within a conserved 9 amino acid motif present in the E domains (ligand binding domain) of progesterone, androgen, and estrogen receptors alpha and beta. In this regard, proteomic approaches have identified heat shock protein 27 as indispensable for sex steroid receptor palmitoylation, as well as trafficking to and signaling from the plasma membrane through various kinase cascades. Signal transduction by estrogen requires membrane-localized ERalpha, a pool that is sufficient for such signaling as recently shown in a mouse that expresses only membrane-localized but no nuclear ERalpha (JBC, 2009). However, complex organ development and function requires nuclear ERalpha. Cell membrane-localized ERbeta is essential to the ability of estrogen to prevent cardiac hypertrophy, in vitro and in vivo. In mitochondria, ERbeta predominates in breast cancer cell lines and with estrogen blocks the ability of radiation or chemotherapy agents to induce apoptotic cell death. This occurs by estrogen/mitochondrial ERbeta stimulating manganese superoxide dismutase activity rapidly, quenching ROS formation that triggers death kinase signaling to the intrinsic mitochondrial apoptosis pathway. We recently implicated these events to underlie tamoxifen resistance in breast cancer models. Localization of steroid receptors to different cellular compartments provides plasticity to respond rapidly or in a more prolonged fashion as appropriate to the demands of the intra or extra-cellular environment.