Fibroblast growth factor 23 (FGF23) and Klotho play key roles, along with serum phosphate and parathyroid hormone (PTH), in disordered mineral metabolism in chronic kidney disease (CKD). Through independent and combined effects on renal phosphorus and vitamin D metabolism, alterations in FGF23 and Klotho expression are essential for maintaining mineral homeostasis in kidney disease. However, increasing evidence showing that disturbances in FGF23 and Klotho expression produce direct cardiovascular and renal toxicity has accelerated interest in therapies that directly target these hormones in the interest of improving outcomes in CKD. Importantly, recent studies showing that reversing CKD-induced elevations in FGF23 levels may have adverse cardiovascular effects have shed new light on the potential unintended consequences linked to developing therapeutic targets in this arena. These findings ultimately support the notion that addressing root causes of disturbances of FGF23 and Klotho, such as phosphorus excess, should remain the main focus in managing mineral metabolism in CKD. © 2013 National Kidney Foundation, Inc.