Selective estrogen receptor modulators (SERMs) inhibit estrogen activation of the estrogen receptor (ER) in some tissues but activate ER in other tissues. These tissue-selective actions suggest that SERMs may be identified with tissue-specificities that would improve the safety of breast cancer and hormone replacement therapies. The identification of an improved SERM would be aided by understanding the effects of each SERM on the structure and interactions of ER. To date, the inability to obtain structures of the full-length ER has limited our structural characterization of SERM action to their anti-estrogenic effects on the isolated ER ligand binding domain. We studied the effects of estradiol and the clinically useful SERMs 4-hydroxytamoxifen and fulvestrant on the conformation of the full-length ER dimer complex by comparing, in living human breast cancer cells, the amounts of energy transfer between fluorophores attached to different domains of ER. Estradiol, 4-hydroxytamoxifen and fulvestrant all promoted the rapid formation of ER dimers with equivalent interaction kinetics. The amino and carboxy terminal ER domains both contain activation functions differentially affected by these ligands, but the positions of only the carboxy termini differed upon binding with estradiol, 4-hydroxytamoxifen or fulvestrant. The association of a specific ER dimer conformation with the binding of ligands of different clinical effect will assist the identification of a SERM with optimal tissue-selective estrogenic and anti-estrogenic activities. These studies also provide a roadmap for dissecting important structural and kinetic details for any protein complex from the quantitative analysis of energy transfer.