Approximately half of the nuclear receptor superfamily have well characterized natural ligands whereas the remaining receptors are considered “orphan” receptors. Many nuclear receptors with identified natural ligands are also validated targets for clinical purposes. Therefore, nuclear receptors are an excellent source for therapeutics aimed at the treatment of a number of diseases, including inflammation, cancer, and metabolic disorders. While there are exceptions to the following description, typically, nuclear receptors are thought to be largely found in the nucleus, bound to DNA, in the absence of ligand. Without ligand, nuclear receptors recruit co-repressor proteins, like NCoR, to silence gene transcription. However, when their cognate ligand binds, a conformational change occurs in the nuclear receptor(s), dissociating the co-repressor protein, enabling the recruitment of co-activator proteins, like SRC1 or SRC2, driving gene transcription.