The estrogen receptors alpha and beta are ligand-activated transcription factors that regulate the magnitude of expression of at least hundreds of genes, and because of their role in a number of diseases, they have often been exploited as targets in medicinal chemistry and drug discovery. Typical antagonism of the estrogen receptor arises from a ligand that induces a conformation of the estrogen receptor that disallows binding of the steroid receptor coactivators, which, along with other coactivators, are responsible for recruiting the basal transcription machinery and for enzymatically repackaging DNA to facilitate gene transcription. Resistance is often seen to these conventional antagonists, and we, and others, have looked to overcome this resistance by directly blocking the estrogen receptor-steroid receptor coactivator interaction by means of a small molecule coactivator binding inhibitor. The literature surrounding these molecules reveals them to be only modestly potent (micromolar) and to be toxic and rather nonselective. We report here four different approaches that we have explored to directly inhibit the estrogen receptor-steroid receptor coactivator interaction. In the first approach (Chapter 2), we have assayed a library of 86,000 compounds in a high-throughput mode using a time-resolved fluorescence resonance energy transfer assay. After a number of secondary and confirmatory assays on hits found in the screen, we discovered a hit possessing a benzothiazole scaffold. Follow-up medicinal chemistry on this compound has revealed a compound having coactivator binding inhibitor activity with an IC50 of 6.3 muM in a luciferase assay. Additionally, this compound is not toxic to HEC-1 cells at concentrations of at least 50 muM, and is slightly selective for estrogen receptor a over estrogen receptor beta and progesterone receptor. In the second approach (Chapter 3), we have tried to more effectively inhibit the interaction of estrogen receptor and steroid receptor coactivator by the recruitment of steric bulk to the interface in the form of the FK-506 binding protein 12. We tethered a molecule, Synthetic Ligand for FK-506 binding protein 12, to an agonist for the estrogen receptor that we hoped would exert antagonistic effects in the presence of the recruited protein. We found, however, that the recruitment of FK-506 binding protein 12 to the estrogen receptor did not inhibit the estrogen receptor-steroid receptor coactivator interaction, but that in an in vitro system, the estrogen receptor was able to accommodate its monomeric partner, a steroid receptor coactivator fragment, a FK-506 binding protein 12-glutathione S-transferase fusion, and, as part of the assay system, a streptavidin-europium conjugate. In the third approach (Chapter 4), we have attempted to use an altered scaffold of a small molecule ("Nutlin") that inhibits a related protein-protein interaction (MDM2-p53) as a coactivator binding inhibitor. We have synthesized, in parallel, a solution-phase library of almost 300 compounds that have molecular subunits that we predicted would bind to the estrogen receptor surface. Unfortunately, these compounds are inactive as coactivator binding inhibitors. In the final approach, we have attempted to design de novo coactivator binding inhibitors based on a benzimidazolone scaffold. These molecules, unfortunately, only weakly bind to the estrogen receptor a.