The ultimate aim of our research is to understand the role of macromolecules in the formation of human kidney stones, particularly their interactions with calcium oxalate (CaOx) crystals. The invariable association of stones with proteins raises the possibility that proteins play a role in their formation, similar to the role of proteins in healthy biomineralization. Do these proteins induce mineralization? Are they merely a response to the disease process? Or are they protective molecules that were overwhelmed by mineral supersaturation? A protein of particular interest is fragment 1 (F1) of prothrombin. We have shown that mRNA for prothrombin is present in the kidney. Because the F1 fragment of prothrombin present in urine is slightly different from that found in the blood, we refer to this protein as "urinary prothrombin fragment 1" (UPTF1). Available evidence suggests that the kidney manufactures the protein for protection against stone disease and that the protein has a directive role in stone formation. We now have evidence that proteins are interred within CaOx crystals precipitated from human urine, where it is distributed in continuous channels. These proteins could facilitate crystal deconstruction and removal after attachment to the renal epithelium and endocytosis. We suspect that the formation of CaOx crystals in the urine is a normal process designed to permit harmless disposal of an excess of calcium, oxalate, or both. The incorporation of proteins provides a second line of defense against stone formation by enabling the destruction and removal of retained crystals. Understanding the basic molecular strategies by which plants produce protein-containing CaOx crystals may provide insight into human CaOx stone formation.