Due to the complexity of estrogen signaling mediated by estrogen receptors (ERs) in a variety of biological environments, there is great interest in the identification and optimization of selective estrogen receptor ligands. Prodrugs that can be activated in specific environments allow for tissue selectivity. Therefore, there have been recent advances in the development of prodrugs for ERs that can be released through enzymatic reactions, chemical reactions (eg, oxidation by reactive oxygen species or reduction by ascorbic acid), or light-mediated processes. In addition, researchers have linked ER ligands to additional drugs for selective cellular targeting. In this review, we highlight the compounds that have been generated and their potential uses in disease states such as breast cancer, inflammation, and menopause.