The molecular interaction of fibroblast growth factor 23 (FGF23) and klotho is essential for physiologic regulation of phosphate balance. In the absence of klotho, the FGF23 protein cannot exert its physiologic functions, as demonstrated by in vivo mouse genetic studies. Bioactive FGF23 protein loses its phosphate lowering effects in genetically modified mice with no klotho activity. The FGF23–klotho system not only affects phosphate homeostasis but can also influence parathyroid hormone (PTH) and vitamin D activities. Dysregulation of the FGF23–klotho system is noted in a number of human acquired and genetic diseases, including chronic kidney disease. Vitamin D is a strong inducer of both FGF23 and klotho expression, while FGF23 can suppress the renal expression of 1α(OH)ase to reduce 1,25(OH)₂D activity. An understanding of the complex interactions of phosphate, vitamin D and PTH with the FGF23–klotho system has paved the way to explore the therapeutic benefits of modulating the FGF23–klotho system in diseases associated with abnormal mineral ion balance. The patent (WO2009095372) under discussion proposes using fusion polypeptides to manipulate the FGF23–klotho system.