Fibroblast growth factor 23 (FGF23) counteracts phosphate excess and tissue calcification. Phosphate intake, Ca(2+), parathyroid hormone, and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) stimulate FGF23 release from bone. FGF23 inhibits renal 1,25(OH)2D3 formation and phosphate reabsorption. Spichtig and colleagues demonstrate that FGF23 is generated in rodent polycystic kidneys, leading to an increase in plasma FGF23 concentration before reduction in kidney function. FGF23 fails to appreciably downregulate renal phosphate transporter and 1α-25OH-vitamin D hydroxylase activities. Unraveling underlying mechanisms may open diagnostic and therapeutic opportunities.