Urine contains compounds that modulate the nucleation, growth and aggregation of crystals as well as their attachment to renal epithelial cells. These compounds may function to protect the kidneys against: 1, the possibility of crystallization in tubular fluid and urine, which are generally metastable with respect to calcium salts, 2, crystal retention within the kidneys thereby preventing stone formation and 3, possibly against plaque formation at the nephron basement membrane. Since oxalate is the most common stone type, the effect of various modulators on calcium oxalate (CaOx) crystallization has been examined in greater details. Most of the inhibitory activity resides in macromolecules such as glycoproteins and glycosaminoglycans while nucleation promotion activity is most likely sustained by membrane lipids. Nephrocalcin, Tamm-Horsfall protein, osteopontin, urinary prothrombin fragment 1, and bikunin are the most studied inhibitory proteins while chondroitin sulfate (CS), heparan sulfate (HS) and hyaluronic acid (HA) are the best studied glycosaminoglycans. Crystallization modulating macromolecules discussed here are also prominent in cell injury, inflammation and recovery. Renal epithelial cells on exposure to oxalate and CaOx crystals produce some of the inflammatory molecules such as monocyte chemoattractant protein-1 (MCP-1) with no apparent role in crystal formation. In addition, macrophages surround the CaOx crystals present in the renal interstitium. These observations indicate a close relationship between inflammation and nephrolithiasis.