In the short time since its initial discovery as the cause of rare hypophosphatemic disorders, fibroblast growth factor-23 (FGF-23) has emerged as a major regulator of mineral metabolism and critical component of the bone and mineral adaptation to CKD. However, because elevated FGF-23 levels are also a novel biomarker and possible molecular mediator of increased risks of cardiovascular disease and death in CKD, the initially adaptive response to increase FGF-23 levels to maintain neutral phosphate balance in CKD may ultimately become maladaptive. Incorporating FGF-23 into understanding the complex physiology that governs normal bone and mineral metabolism and its alterations in CKD has filled critical knowledge gaps and opened a new landscape of exciting hypotheses and novel therapeutic strategies to be tested in the continued quest to alleviate the burden of CKD.