Klotho is a protein that exerts paracrine and endocrine functions. In chronic kidney disease (CKD), its expression is decreased in several tissues. This decrease probably plays important roles in various complications associated with CKD, in both a fibroblast growth factor-23 (FGF23)-dependent and an FGF23-independent manner. The clinical diagnosis of Klotho deficiency is not easy. The relevance of circulating Klotho levels, if any, needs to be adequately defined. Serum Klotho may not reflect tissue Klotho concentration.