This work details recent advances in the science of estrogen receptor (ER) modulation, with emphasis on the discovery of novel ligands for the ER ligand binding domain (LBD). A detailed examination of structural studies of the ERs is presented with analysis of the impact of such works on contemporary ligand design and the molecular pharmacology of the ER. The various classes of ER modulators are discussed on the basis of stuctural similarities including selective estrogen receptor modulators (SERMs) and ‘pure’ nonsteroidal antiestrogens. Additionally we review the emergence of a novel selective class of modulator - which we have termed the selective estrogen receptor subtype modulators (SERSMs) and, in a departure from LBD strategies we examine the discovery of novel peptide inhibitors of the ER which inhibit transcriptional activiation of agonist liganded receptor through interaction with coactivator recruitment proteins, and offer unique insight to the mechanism of action of all classes of ER modulators. Through examination of patent and classical literature we present a thorough and informative cross-section of the contemporary state of the art in this exciting field of pharmaceutical research.