A malfunction in regulatory circuit of many transcription factors have been implicated as the primary cause of a wide array of diseases including developmental disorders, inflammation, allergies and asthma, cancers, diabetes, cardiovascular problems, and neurological disorders. As a result, identifying the binding preferences of transcription factors is crucial for targeting therapeutic interventions for diseases. The major goal of this project is to computationally detail and experimentally validate the complex DNA binding patterns of Nuclear Receptor (NR) class of transcription factors, with an especial focus on unmasking the impact of co-factors, natural ligands, as well as synthetic therapeutic molecules and widely prescribed drugs.