The calcium-sensing receptor (CaR) and the vitamin D receptor (VDR) play key roles in calcium homeostasis. The CaR regulates the release of parathyroid hormone (PTH) in response to changes in extracellular calcium, whereas the VDR mediates the effects of calcitriol, the active metabolite of vitamin D. The development of secondary hyperparathyroidism (HPT) is a common complication of chronic kidney disease. Secondary HPT is characterized by disturbances in mineral metabolism, elevated serum PTH, and parathyroid gland hyperplasia. Alterations in CaR and VDR expression and activation play central roles in the development of secondary HPT. The impact of any nutritional and pharmacologic intervention on these two receptors should be carefully considered, to optimize patient outcomes. The important roles of CaR and VDR in the pathogenesis of secondary HPT are demonstrated by the complex interactions between their respective signaling pathways.