Aim: To study the potential mechanisms underlying the beneficial nephroprotective effects of sodium-glucose cotransporter 2 (SGLT-2) inhibitors. Materials and Methods: An analysis of literature sources was conducted regarding the clinical, epidemiological, and fundamental aspects of the nephroprotective effects of SGLT-2 inhibitors. For this purpose, articles were searched for and selected in the PubMed database using the following keywords: “sodium-glucose cotransporter-2 inhibitors,” “heart failure,” “chronic kidney disease,” and “cardiorenal syndrome,” with a primary focus on studies published in the last 5 years. To provide context and explain the underlying mechanisms, several classical and fundamental studies relevant to the aim of the review were also included. Conclusions: SGLT-2 inhibitors exert nephroprotective effects through a complex of interrelated hemodynamic, metabolic, and cellular-molecular mechanisms that are largely independent of their hypoglycemic action. The combination of these mechanisms explains the clinically proven nephroprotective effect of SGLT-2 inhibitors in both patients with and without DM and justifies considering them not only as glucose-lowering agents but also as fundamental agents of pathogenetic therapy for chronic kidney disease.