Calcium oxalate (CaOx) urolithiasis is a very common disorder. Surprisingly, the pathogenetic mechanisms leading to CaOx stone formation have been largely unknown so far. The long-accepted simple explanation by an exceeding of the solubility product of lithogenic substances in the urine cannot sufficiently describe the complex processes. Deviating from the hypothesis that proclaims that the initial crystal deposition takes place in the lumens of renal tubules, new insights suggest a primary plaque formation in the interstitial space of the renal papilla. Initially, calcium phosphate (CaPh) crystals and organic matrix are deposited along the basement membranes of the thin loops of Henle and extend further in the interstitial space to the urothelium, constituting the so-called Randall's plaques that can be regularly found during endoscopy of CaOx-stone-forming patients. These CaPh crystals seem to be the origin for the development of future CaOx stones, which form by the attachment of further matrix molecules and CaOx from the urine to the plaque. The driving forces, the exact pathogenetic mechanisms, and the involved matrix molecules remain largely unknown. Possibly, completely different pathomechanisms lead to the common clinical diagnosis of"CaOx stone former."