Exploitation of the relationship between estrogen receptor (ER) structure and activity has led to the development of 1) selective ER modulators (SERM), compounds whose relative agonist/antagonist activities differ between target tissues; 2) selective ER degraders (SERD), compounds that induce a conformational change in the receptor that targets it for proteasomal degradation; and 3) tissue-selective estrogen complexes (TSEC), drugs in which a SERM and an ER agonist are combined to yield a blended activity that results in distinct clinical profiles. In this study, we have performed a comprehensive head-to-head analysis of the transcriptional activity of these different classes of ERM in a cellular model of breast cancer. Not surprisingly, these studies highlighted important functional differences and similarities among the existing SERM, selective ER degraders, and TSEC. Of particular importance was the identification of genes that were regulated by various TSEC combinations but not by an estrogen or SERM alone. Cumulatively, the findings of this analysis are informative with respect to the mechanisms by which ER is engaged by different enhancers/promoters and highlights how promoter context influences the pharmacological activity of ER ligands.