Klotho is a single-pass transmembrane protein that is highly expressed in the kidney and is known to act as a coreceptor for fibroblast growth factor 23. The extracellular domain can be produced independently or shed from membrane-bound Klotho and functions as an endocrine substance with multiple functions including antioxidation, modulation of ion transport, suppression of fibrosis, and preservation of stem cells. Emerging evidence has revealed that Klotho deficiency is an early event in acute kidney injury (AKI), and a pathogenic factor that exacerbates acute kidney damage and contributes to long-term consequences. Restoration by exogenous supplementation or stimulation of endogenous Klotho might prevent and ameliorate injury, promote recovery, and suppress fibrosis to mitigate development of chronic kidney disease. Although data are still emerging, in this Perspectives article we discuss why this renal-derived protein is a highly promising candidate as both an early biomarker and therapeutic agent for AKI.