alpha-Klotho was first identified as the responsible gene in a mutant mouse line whose disruption results in a variety of premature aging-related phenotypes. alpha-Klotho has been shown to participate in the regulation of parathyroid hormone secretion and trans-epithelial transport of Ca(2+) in the choroid plexus and kidney. alpha-Klotho, acting as a cofactor for FGF23, is also a major regulator of vitamin D biosynthesis and phosphate reabsorption in the kidney. These suggest that alpha-Klotho is a key player that integrates a multi-step regulatory system of calcium and phosphate homeostasis. Collectively, the molecular function of alpha-Klotho reveals a new paradigm that may change current concepts in mineral homeostasis and give rise to new insights in this field.