This review summarizes and critically analyzes current data on the pathogenesis of urolithiasis (urolithiasis, nephrolithiasis). Emphasis is placed on such issues as: mechanisms of urinary stone formation; risk factors for stone formation; the role of oxidative stress; the chemical composition of renal stones (and especially oxalates); the role of Randall’s plaques, osteopontin, uromodulin (Tamm–Horsfall protein), α-enolase; and the mechanism of stone formation in the collecting ducts. Insufficiently studied issues of microbiota influence — (a) kidney and urinary tract and (b) gastrointestinal tract are also considered. Attention is paid to new approaches to understanding the pathogenesis and treatment of urolithiasis, namely works on genetics, epigenetics, genetic engineering and proteomics. The imperfection of existing animal models of urolithiasis is shown. The issue of application of androgen replacement therapy in the treatment of patients suffering from urolithiasis is considered separately. The author considers the main theoretical result of his work to be the approval of the idea of urolithiasis as a systemic disease, in which any significant deviation of the internal environment constants violates the delicate balance that ensures the solubility of substances in primary urine and their excretion with secondary urine. The practical result is to confirm the applicability of androgen replacement therapy in the treatment of patients suffering from urolithiasis.