Calcium oxalate (CaOx) nephrolithiasis is a common and complex kidney stone disease with intricate formation mechanisms. It primarily originates from interstitial subepithelial calcified plaques (Randall's plaques) and/or calcified blockages in the openings of collecting ducts. These calcified structures come into contact with urine in the renal pelvis, acting as a nidus for crystal formation and subsequent stone growth. Both pathways share similar mechanisms, including abnormal urine composition, oxidative stress, inflammation, and imbalances in stone inhibitors and promoters. However, they also have unique characteristics. This review aims to provide a detailed description of the formation processes of calcareous nephrolithiasis from two distinct origins: the renal interstitium and the tubule lumen. Abnormal urine solute concentrations, such as hypercalciuria, hyperoxaluria, and hypocitraturia, play a critical role in driving stone formation. Hypercalciuria is the most common abnormality in stone-forming patients, affecting 30%-60% of individuals. Hyperoxaluria is a significant contributor to the supersaturation of CaOx in urine. Hypocitraturia is also strongly associated with stone formation and is present in approximately 20%–60% of patients with calcium stones. Urinary citrate inhibits calcium stone formation by binding with urinary calcium, reducing ionized calcium concentration and interfering with calcium crystal nucleation and growth. Oxidative stress and inflammation are important factors in the pathogenesis of urolithiasis. These processes are involved in multiple steps of stone formation, including injury and death of tubular epithelial cells, epithelial-to-osteoblast transformation, calcification of the vasa recta, collagen mineralization, macrophage recruitment and crystal clearance, disruption of the urothelium, and production of crystallization modulating macromolecules. Clinical data show that patients with calcium oxalate stones have higher levels of injury markers, inflammatory and proinflammatory cytokines, and lower antioxidant levels in their urine. Calcified plaques in the renal interstitium (Randall's plaques) are formed through various mechanisms, including CaP deposition in basement membranes, vascular calcification, and epithelial-to-osteoblast transformation. These plaques eventually grow and break through the urothelium, coming into contact with urine and serving as a nidus for CaOx stone formation. The growth of calcified plaques is facilitated by the mineralization process of collagen. Macrophages play a crucial role in renal tissue inflammation, damage, and fibrosis in various kidney diseases. Calcified aggregates in the renal tubular lumen (Randall's plugs) are commonly observed in patients with various types of kidney stones. These aggregates block the openings of the Bellini ducts and form Randall's plugs. Over time,Calcium oxalate (CaOx) nephrolithiasis is a common and complex kidney stone disease with intricate formation mechanisms. It primarily originates from interstitial subepithelial calcified plaques (Randall's plaques) and/or calcified blockages in the openings of collecting ducts. These calcified structures come into contact with urine in the renal pelvis, acting as a nidus for crystal formation and subsequent stone growth. Both pathways share similar mechanisms, including abnormal urine composition, oxidative stress, inflammation, and imbalances in stone inhibitors and promoters. However, they also have unique characteristics. This review aims to provide a detailed description of the formation processes of calcareous nephrolithiasis from two distinct origins: the renal interstitium and the tubule lumen. Abnormal urine solute concentrations, such as hypercalciuria, hyperoxaluria, and hypocitraturia, play a critical role in driving stone formation. Hypercalciuria is the most common abnormality in stone-forming patients, affecting 30%-60% of individuals. Hyperoxaluria is a significant contributor to the supersaturation of CaOx in urine. Hypocitraturia is also strongly associated with stone formation and is present in approximately 20%–60% of patients with calcium stones. Urinary citrate inhibits calcium stone formation by binding with urinary calcium, reducing ionized calcium concentration and interfering with calcium crystal nucleation and growth. Oxidative stress and inflammation are important factors in the pathogenesis of urolithiasis. These processes are involved in multiple steps of stone formation, including injury and death of tubular epithelial cells, epithelial-to-osteoblast transformation, calcification of the vasa recta, collagen mineralization, macrophage recruitment and crystal clearance, disruption of the urothelium, and production of crystallization modulating macromolecules. Clinical data show that patients with calcium oxalate stones have higher levels of injury markers, inflammatory and proinflammatory cytokines, and lower antioxidant levels in their urine. Calcified plaques in the renal interstitium (Randall's plaques) are formed through various mechanisms, including CaP deposition in basement membranes, vascular calcification, and epithelial-to-osteoblast transformation. These plaques eventually grow and break through the urothelium, coming into contact with urine and serving as a nidus for CaOx stone formation. The growth of calcified plaques is facilitated by the mineralization process of collagen. Macrophages play a crucial role in renal tissue inflammation, damage, and fibrosis in various kidney diseases. Calcified aggregates in the renal tubular lumen (Randall's plugs) are commonly observed in patients with various types of kidney stones. These aggregates block the openings of the Bellini ducts and form Randall's plugs. Over time,