Until 1986, our understanding of estrogen receptor (ER) action was based on information derived from in vitro biochemical analyses and in vivo correlations. With the cloning of the human ER cDNA, the reconstitution of ER responsive transcription units in heterologous cells has permitted the genetic dissection of the ER signal transduction pathway. The recent discovery of ER beta and a multitude of adaptor proteins (coactivators and corepressors) has expanded the potential explanation for tissue-selective activities. The current concept of ER action includes a rheostat-like action of the receptor due to conformational changes in the ligand receptor complex that depend on the nature of the bound ligand. This conformational change also determines subsequent adaptor protein interactions. Recognition of the tissue-specific activities of tamoxifen, the first selective ER modulator (SERM), led to the development of new SERMs (raloxifene and toremifene) with greater tissue selectivities. A knowledge of the key adaptor proteins expressed within each ER target cell will allow mechanism-based screening of selective ER modulators. These future "designer estrogens" of the next millennium will be used for specific applications in the central nervous, cardiovascular, bone and reproductive systems.