Nuclear receptors, or NRs, are transcription factors that bind ligands, such as hormones, lipids, and vitamins, to alter gene expression. Currently, they are targeted by nearly 15% of approved drugs. NRs can be of two main classes: Class I NRs are cytosolic. They bind steroid hormones and undergo dimerization. The homodimers translocate to the nucleus and interact with DNA response elements, recruiting co-activators or co-repressors. Co-activators recruit enzymes to unzip the DNA helix to initiate transcription. In contrast, co-repressors use enzymes to keep the DNA tightly packed, blocking transcription. For example, tamoxifen selectively blocks estrogen receptors or ERs and helps treat ER-positive breast tumors. Class II NRs exist in the nucleus as DNA-bound heterodimers with retinoid X receptors and remain bound to co-repressors When a lipid ligand binds these NRs, the co-repressors detach, and a co-activator is recruited. Fenofibrate, a lipid-lowering drug, binds class II NRs like PPAR to activate genes that regulate fatty acid metabolism and decrease plasma triglyceride levels.