The pathogenesis of calcium-oxalate (CaOx) renal stones is still debated and a number of issues needs to be clarified. In particular, it is difficult to combine the intraluminal physical-chemical imbalance and fixed particle theory with the evidence that CaOx stones actually form and grow on Randall's plaque in the renal pelvis. On the basis of recent findings in renal stone research, and data from the biology of ectopic calcification, the hypothesis is advanced that abnormal pre-urine CaOx supersaturation triggers inflammation in the long Henle's loop cells at tip forceps level. This in turn induces differentiation of these cells toward the osteogenic lineage, determining the synthesis of typical bone osteoid proteins (osteopontin, osteocalcin, BMP-2, etc) and hydroxyapatite mineralization of the Henle's basement membrane (beneath the differentiating cells) which precedes Randal's plaque formation. This may constitute a further, still unexplored example of epithelial-mesenchymal-differentiation in the kidney.