Nuclear Receptors (NRs) are small molecule-activated transcription factors and key drivers of cancer pathology. Because NR genomic activities are highly dependent on the binding of small molecules to reprogram transcription, they are ideal therapeutic targets for a diverse range of diseases. In fact, 16% of all FDA approved drugs target NRs. Our goal is to understand how small molecules influence NR structures, alter their genomic activities, and achieve breast cancer-specific therapeutic endpoints. These structures enable the rational design of improved therapeutic small molecules which will be used as anti-cancer agents to address the unmet therapeutic needs of breast cancer patients.