In addition to their well known control of reproductive functions, estrogens modulate important physiological processes. The identification of compounds with tissue-selective activity will lead to new drugs mimicking the beneficial effects of estrogen on the prevention of osteoporosis and cardiovascular or neurodegenerative diseases, while avoiding its detrimental proliferative effects. As an innovative model for the in vivo identification of new selective estrogen receptor modulators (SERMs), we engineered a mouse genome to express a luciferase reporter gene ubiquitously. The constructs for transgenesis consist of the reporter gene driven by a dimerized estrogen-responsive element (ERE) and a minimal promoter. Insulator sequences, either matrix attachment region (MAR) or β-globin hypersensitive site 4 (HS4), flank the construct to achieve a generalized, hormoneresponsive luciferase expression. In the mouse we generated, the reporter expression is detectable in all 26 tissues examined, but is induced by 17β-estradiol (E₂) only in 15 of them, all expressing estrogen receptors (ERs). Immunohistochemical studies show that in the mouse uterus, luciferase and ERs colocalize. In primary cultures of bone marrow cells explanted from the transgenic mice and in vivo, luciferase activity accumulates with increasing E₂ concentration. E₂ activity is blocked by the ER full antagonist ICI 182,780. Tamoxifen shows partial agonist activity in liver and bone when administered to the animals. In the mouse system here illustrated, by biochemical, immunohistochemical, and pharmacological criteria, luciferase content reflects ER transcriptional activity and thus represents a novel system for the study of ER dynamics during physiological fluctuations of estrogen and for the identification of SERMs or endocrine disruptors. . At the present time, molecules active through estrogen receptors (ERs) are used in fertility control, endocrine dysfunction, and cancer therapy. In postmenopausal women, estrogen replacement therapy (2) was proven efficacious for the prevention of osteoporosis (3), and several lines of study suggested that 17β-estradiol (E₂) has beneficial effects in cardiovascular (4, 5) and selected neurodegenerative diseases (6). Unfortunately, the prolonged use of this hormone has been associated with increased risk of breast and uterine cancer (7). The discovery that synthetic ligands of the ER may exhibit tissue-specific agonist or antagonist activity raised a new interest in the use of these compounds for estrogen replacement therapy (8, 9). These selective estrogen receptor modulators or SERMs are identified by comparative screening in cells of different origin to characterize their tissue-specific profile (agonist/antagonist). Generally, the study is carried out in transformed cell lines stably or transiently transfected with ERα or -β and a reporter of the receptor’s activated state. In addition to limiting the analysis to a selected number of cells, this method may also provide erroneous or defective results. In fact, the tissue-specific agonist/antagonist activity of SERMs has been attributed to the presence of cell-specific proteins capable of interacting with the hormone receptor complex (10), and these proteins may be aberrantly expressed in cancer cells (11). Thus, the major shortcoming of this screening procedure is associated with the requirement of further in vivo analysis for the identification of the pharmacodynamic properties of the molecule to be developed. The availability of an engineered mouse carrying an ER reporter expressed ubiquitously as a transgene would represent a remarkable advancement for the identification and profiling of new SERMs. In addition …