Sodium-glucose cotransporter 2 (SGLT2) inhibitors have proven cardiorenal protection in patients with diabetes and chronic kidney disease (CKD) as seen in cardiovascular outcome trials (CVOTs) and CREDENCE. In this review, we aim to discuss the mechanisms of kidney protection with SGLT2 inhibition as well as review the results of multiple translational studies and clinical trials of SGLT2 inhibition in the nondiabetic kidney disease (non-DKD) population. The application of SGLT2 inhibitors as dedicated kidney-protective agents continues to evolve with the publication of the dapagliflozin in patients with chronic kidney disease (DAPA CKD) trial, which extends their cardiorenal protection to patients with nondiabetic CKD. This trial was preceded by CREDENCE, a dedicated kidney outcome study in participants with DKD that demonstrated a 30% reduction in the risk of the composite kidney outcome. From a physiological perspective, mechanistic benefits of SGLT2 inhibitors are independent of their glucose-lowering effects as demonstrated in preclinical studies and post hoc analyses of dedicated CVOTs in participants with type 2 diabetes. From a clinical perspective, there is a growing body of evidence for kidney protection in nondiabetes mellitus patients. There exists strong rationale for SGLT2 inhibition to be incorporated into standard of care for appropriate groups of patients with nondiabetic kidney disease.