Hyperphosphatemia has consistently been shown to be associated with dismal outcome in a wide variety of populations, particularly in chronic kidney disease (CKD). Compelling evidence from basic and animal studies elucidated a range of mechanisms by which phosphate may exert its pathological effects and motivated interventions to treat hyperphosphatemia. These interventions consisted of dietary modifications and phosphate binders. However, the beneficial effects of these treatment methods on hard clinical outcomes have not been convincingly demonstrated in prospective clinical trials. In addition, exposure to high amounts of dietary phosphate may exert untoward actions even in the absence of overt hyperphosphatemia. Based on this concept, it has been proposed that the same interventions used in CKD patients with normal phosphate concentrations be used in the presence of hyperphosphatemia to prevent rise of phosphate concentration and as an early intervention for cardiovascular risk. This review describes conceptual models of phosphate toxicity, summarizes the evidence base for treatment and prevention of hyperphosphatemia, and identifies important knowledge gaps in the field.