Nuclear receptors (NRs) play a key role in many cellular functions through specific gene expression regulation and are targeted by a large number of both endogenous and exogenous ligands. The estrogen receptor (ER), a member of the nuclear receptor family, mainly acts as a DNA-binding transcription factor. The estrogen receptor exists primarily in two isoforms: ERα and ERβ. The distribution of the two isoforms is not uniform amongst all tissue types and allows for a means of selectively targeting specific tissues such as breast or bone tissue. In addition, ER ligands can possess different degrees of agonistic/antagonistic function within different tissue types – leading to the paradigm of what is referred to as selective estrogen receptor modulator (SERM) and selective estrogen receptor subtype modulator (SERSM) ligands. Advances in the area of structural biology, coupled with improved computational resources, has lead to a greater degree of information and knowledge regarding the estrogen receptor and its complex mode of action. A number of high-affinity binding, estrogen-receptor ligands have been developed – greatly aided through the combined implementation of crystallography, structural biology and medicinal chemistry processes. In this review, examples of the more recently developed benzopyran-, benzoxepin-, diphenylamine-,anthranylaldoxime-, salicylaldoxime-, benzisoxazole- chroma-quinoline-, dihydronezoxathiins-, dihydrobenzo-dithiins-, tetrahydrofluorenone-, indazole- and benzoxazole-based SERMs and SERSMs are discussed with the aim of highlighting the key points of the structure-activity relationship and development stages involved in achieving potent and selective ER ligands.