The classical models of steroid receptor pharmacology held that agonists functioned by binding to their cognate receptors, facilitating their conversion from an inactive form to one that was capable of activating transcription. By extrapolation, it was believed that antagonists functioned by competitively inhibiting agonist binding, freezing the receptor in an inactive state. However, as early as 1967 when the biologic actions of the "antiestrogen" tamoxifen were first described, it was clear that this simple model did not adequately describe estrogen receptor (ER) pharmacology. Since these initial observations, significant progress has been made in defining the molecular mechanism(s) by which cells distinguish between different ER ligands. The most important of these are: (i) differences in the relative expression level of the two ER subtypes, alpha and beta, in target tissues; (ii) the impact, which the bound ligand has on ER structure; and (iii) the complement of coactivators and corepressors in a target cell, which can interact with the activated receptor. This review describes how these advances have impacted our understanding of the pharmacologic activities of currently available ER ligands.