Observational studies have determined hyperphosphatemia to be a cardiovascular risk factor in chronic kidney disease. Mechanistic studies have elucidated that hyperphosphatemia is a direct stimulus to vascular calcification, which is one cause of morbid cardiovascular events contributing to the excess mortality of chronic kidney disease. This review describes the pathobiology of hyperphosphatemia that develops as a consequence of positive phosphate balance in chronic kidney disease and the mechanisms by which hyperphosphatemia acts on neointimal vascular cells that are stimulated to mineralize in chronic kidney disease. The characterization of hyperphosphatemia of chronic kidney disease as a distinct syndrome in clinical medicine with unique disordered skeletal remodeling, heterotopic mineralization and cardiovascular morbidity is presented.Hyperphosphatemia is associated with significant pathophysiology in chronic kidney disease (CKD). This pathophysiology contributes to the high rates of mortality observed in CKD (1). Approximately 11–15% of Americans have CKD (2–4), and their risk of death due to a cardiovascular event related cause is higher than their risk of surviving and needing renal replacement therapy for end stage kidney disease (ESKD) (1,2,4). The mortality rates of patients surviving CKD and receiving hemodialysis are extremely high such that a 30 year old patient with ESKD has a life expectancy similar to a ninety year old with normal renal function (2). The mechanisms of this excess risk of cardiovascular disease are not completely understood. The well characterized risks of cardiovascular disease in the general population do not explain the increased risk in CKD (1,3). Observational studies suggest that the well known propensity of ESKD patients to develop heterotopic mineralization of soft tissues including the vasculature is an important component of the cardiovascular risks of ESKD (5, 6). Furthermore, several observational studies demonstrate that hyperphosphatemia is an independent cardiovascular risk factor in CKD (7–9). Hyperphosphatemia has been linked to vascular calcification (5,10)(11).