Nuclear receptors are transcription factors that are essential in embryonic development, maintenance of differentiated cellular phenotypes, metabolism, and apoptosis. Dysfunction of nuclear receptor signaling leads to a wide spectra of proliferative, reproductive, and metabolic diseases, including cancers, infertility, obesity, and diabetes. In addition, many proteins have been identified as coregulators which can be recruited by DNA-binding nuclear receptors to affect transcriptional regulation. The cellular level of coregulators is crucial for nuclear receptor-mediated transcription and many coregulators have been shown to be targets for diverse intracellular signaling pathways and posttranslational modifications. This review provides a general overview of the roles and mechanism of action of nuclear receptors and their coregulators. Since progression of renal diseases is almost always associated with inflammatory processes and/or involve metabolic disorders of lipid and glucose, cell proliferation, hypertrophy, apoptosis, and hypertension, the importance of nuclear receptors and their coregulators in these contexts will be addressed.