The most common form of renal stone disease, calcium nephrolithiasis, is defined as the presentation of a macroscopic concrement of inorganic (calcium phosphate and/or calcium phosphate) and organic material in the renal calyces and/or pelvis, either adhered to the papillae or pelvic urothelium or not. In search of the mechanism underlying calcium nephrolithiasis, in vitro and in vivo studies and observations in human biopsies have shown the presence of two distinct types of renal microscopical crystal deposition processes; one taking place within the tubular lumen (intratubular nephrocalcinosis), and the other in the interstitium (interstitial nephrocalcinosis). Recent observations, however, strongly suggest that nephrocalcinosis and calcium nephrolithiasis are to be considered two independent pathologies and that nephrocalcinosis may cause calcium nephrolithiasis only in particular conditions. In this review, we discuss our current understanding of the mechanisms involved in both types of nephrocalcinosis (intratubular and interstitial), their possible consequences and their relation to calcium nephrolithiasis.