OBJECTIVE The study of phosphorus physiology and investigations into clinical disorders of phosphorus metabolism has blossomed over the past decade. Recent work has confirmed and further extended our knowledge of basic mechanisms of phosphorus metabolism. RESULTS This review will focus on FGF-23 and Klotho, and on the recent further dissection of their roles in phosphorus and skeletal metabolism. Additionally, this review will detail recent studies that implicate a role for these phosphaturic and vitamin D regulating factors in extraskeletal calcification, including that occurring in soft tissue and vascular beds. CONCLUSIONS These findings in total provide fertile ground for investigations into the cause and treatment of abnormal skeletal and extraskeletal calcification in patients with inherited hypophosphatemic disorders. More importantly, and certainly with wider potential clinical application, these studies likewise imply a role for these factors in the pathogenesis of accelerated cardiovascular disease that occurs in patients with the most common hyperphosphatemic disorder, chronic kidney disease. Future studies are needed to confirm a harmful or possibly even beneficial role for FGF-23 and other factors in these disease states, and to determine whether therapeutic manipulation of these factors does truly affect clinical outcomes in patients with hypophosphatemia and hyperphosphatemia.