Background: Several organs such as the skin and liver have a great capacity for regeneration. However, many approaches only delay the progression of end-stage kidney disease and do not achieve efficient long-term stabilization, let alone regeneration. Summary: In mammals, the kidney has an innate but limited capacity for regeneration which can only modify the nephron structure and function but not increase the nephron number. Several clinical and animal studies have indicated that functional improvements and/or structural regression can occur in chronic kidney disease. Cell reconstitution, matrix remodeling, and tissue reorganization are major mechanisms for kidney regeneration. Current approaches achieve only partial kidney regeneration, but this does not occur in all animals and is not sustained in the long term. Multipronged and early interventions are future choices for the induction of kidney regeneration. Key Messages: Kidney regeneration in mammals is feasible but limited and may be enhanced by multitargeting key mechanisms.