The actions of estrogens are mediated through the two estrogen receptors, ERalpha and ERbeta. Compounds that interact selectively with ERalpha or ERbeta are of interest because they could be used to explore the biological roles of these ER subtypes and they might be interesting estrogen pharmaceuticals. In a new approach to develop ER subtype-selective ligands, we have embellished the 1,1-diarylethylene motif, common to many nonsteroidal estrogens, with various bridged bicyclic or tricyclic cores, including ones based on bicyclo[3.3.1]nonane, bicyclo[2.2.1]heptane, and selected bi- and tricyclic terpenoids. This design leads to three-dimensional ER ligands of unusual structure that we have used to probe the size and shape of the ligand binding pocket of ERalpha and ERbeta. Many of these compounds have high binding affinities, with the best having a bicyclo[3.3.1]nonane core and binding 3-5 times better than estradiol to both ER subtypes. Some of the compounds show significant affinity selectivity in favor of ERbeta (4- to 5-fold), and in cell-based assays for transcriptional activity most are partial agonists on ERalpha and full antagonists on ERbeta.