Hyperphosphatemia in chronic kidney disease (CKD) is considered as an independent risk factor for surrogate clinical end points like vascular calcification (VC) and bone disease, or hard clinical outcomes like cardiovascular events. Various treatment options are available for phosphate removal or reduction. Calcium-based phosphate binders (CBB) with their possible positive calcium balance became culprits for progressive VC and increased mortality risk. Non-calcium-based binders (NCBB) treatment allowed a comparable control of hyperphosphatemia with a lower risk of hypercalcemia and a slower progression of VC. Recent data have shown a 22% risk reduction in all-cause mortality with NCBB compared to CBB treatment. The appropriate timing of phosphate binder initiation in CKD patients is still unclear. Recent reports in patients with CKD stages 3b-4 showed increased VC progression when actively treated compared to placebo and a positive calcium, but no negative phosphate balance. This review discusses the advantages and disadvantages of the pharmacological options to treat hyperphosphatemia. The use of phosphate binders is essential in preventing morbidity and mortality in dialysis patients. The choice of phosphate binder takes into account CKD stage, the presence of other components of CKD-mineral and bone disorders, concomitant therapies and drug side-effect profile.