The kidney has extraordinary metabolic demands to sustain the active transport of solutes that is critical to renal filtration and clearance. Mitochondrial health is vital to meet those demands and maintain renal fitness. Decades of studies have linked poor mitochondrial health to kidney disease. Key regulators of mitochondrial health-adenosine monophosphate kinase, sirtuins, and peroxisome proliferator-activated receptor γ coactivator-1α-have all been shown to play significant roles in renal resilience against disease. This review will summarize the latest research into the activities of those regulators and evaluate the roles and therapeutic potential of targeting those regulators in acute kidney injury, glomerular kidney disease, and renal fibrosis.