Fibroblast growth factor 23 (FGF23) was recently recognized as a major hormone regulating phosphate homeostasis and has been directly linked to cardiovascular disease and all cause mortality in chronic kidney disease. FGF23 rises in patients with kidney disease before other disturbances of mineral homeostasis are detectable. In patients with autosomal dominant polycystic kidney (ADPKD) the rise in FGF23 precedes even the first measurable decline in renal function. The mechanisms regulating FGF23 production and effects in kidney disease are largely unknown. In the current study, we measured FGF23 expression in an ADPKD rat model (Han:SPRD). Compared to healthy controls, in mutant animals serum FGF23 levels were significantly increased from week 2 after birth, while renal function was still normal. Increased FGF23 was mainly produced by bone but ectopic mRNA expression was detected in kidney, spleen and liver. Although circulating FGF23 was highly upregulated, serum phosphate and calcium levels in mutant animals were normal, and the expression of renal phosphate transporters and Cyp27b1 in kidney was similar compared to controls indicating FGF23 resistance in peripheral FGF23 sensitive tissues. FGF23 resistance in kidney may be caused by reduced Klotho expression, the obligate co-receptor of the FGF receptor for FGF23. Our data demonstrate a correlation between FGF23 expression and chronic kidney disease progression and indicate that FGF23 may play other roles besides calcium and phosphate regulation in kidney disease.