Nuclear receptor (NR) liver receptor homologue-1 (LRH-1) is a potential target for the treatment of breast cancers as a consequence of its regulation of aromatase and the estrogen receptor (ER). Development of modulators of NRs historically focuses on production of high affinity small molecules that compete for binding with natural ligands at the ligand-binding pocket (LBP) of the NR ligandbinding domain (LBD). Ligand-bound NRs induce transcriptional activity by subsequent recruitment of coactivator proteins. The majority of this thesis describes approaches towards the development of the first antagonists of LRH-1. In the first instance, small molecules that bind at the LBP of the receptor were developed through use of ligand-based virtual screening (VS) programs Cresset and SHop. Secondly, small molecules that directly disrupt the binding of cofactor proteins to the NR activation function-2 (AF-2) were developed through use of rational design and further Cresset VS.