The purpose of these studies was to test the hypothesis that Randall’s plaque develops in unique anatomical sites of the kidney and that its formation is conditioned by specific stone-forming pathophysiologies. To test this hypothesis, we performed intraoperative mapping studies with biopsies of papilla from the kidneys of 15 idiopathic calcium oxalate (CaOx) stone formers, four intestinal bypass for obesity patients and ten brushite stone formers, and obtained papillary specimens from four non-stone formers after nephrectomy. Both light and electron microscopic examination of tissue changes along with infrared and electron diffraction analyses of mineral composition were performed. Distinct patterns of mineral deposition and papillary pathology were discovered in each of the three different stone forming groups. CaOx stone formers had predictable sites of interstitial apatite crystals beginning at the thin loops of Henle and spreading to the urothelium. These plaque areas are termed Randall’s plaque and are thought to serve as sites for stone attachment. The papilla and medullary tubules appeared normal. The intestinal bypass patients only had intraluminal sites of crystalline material in the medullary collecting ducts. The brushite stone formers had the most severe form of cortical and medullary changes with sites of Randall’s plaque, and yellowish intraluminal deposits in medullary collecting ducts. All deposits were determined to be apatite. The metabolic and surgical pathologic finding in three distinct groups of stone formers clearly shows that “the histology of the renal papilla from a stone former is particular to the clinical setting”. It is observations like these that we believe will provide the insights to allow the stone community to generate better clinical treatments for kidney stone disease, as we understand the pathogenesis of stone formation for each type of stone former.