The kidney plays a major role in maintenance of serum calcium concentration, which must be kept within a narrow range to avoid disruption of numerous physiologic processes that depend critically on the level of extracellular calcium, including cell signaling, bone structure, and muscle and nerve function. This defense of systemic calcium homeostasis comes, however, at the expense of the dumping of calcium into the kidney tissue and urine. Because of the large size and multivalency of the calcium ion, its salts are the least soluble among all the major cations in the body. The potential pathologic consequences of this are nephrocalcinosis and kidney stone disease. In this review, we discuss recent advances that have highlighted critical roles for the proximal tubule and thick ascending limb in renal calcium reabsorption, elucidated the molecular mechanisms for paracellular transport in these segments, and implicated disturbances in these processes in human disease.