In spite of excellent glucose and blood pressure control, including administration of angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers, diabetic nephropathy (DN) still develops and progresses. The development of additional protective therapeutic interventions is, therefore, a major priority. Nuclear hormone receptors regulate carbohydrate metabolism, lipid metabolism, the immune response, inflammation and development of fibrosis. The increasing prevalence of DN has led to intense investigation of the role that nuclear hormone receptors may have in slowing or preventing the progression of renal disease. Several nuclear receptor-activating ligands (agonists) have been shown to have a renal protective effect in the context of DN. This review will discuss the evidence regarding the beneficial effects of the activation of the vitamin D receptor (VDR) and the farnesoid X receptor (FXR) in preventing the progression of DN, and will describe how the discovery and development of compounds that modulate the activity of VDR and FXR may provide potential additional therapeutic approaches in the management of DN.