Phosphate levels are strikingly associated with poor outcomes in chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. Numerous epidemiological studies have repeatedly documented a worrisome link between serum phosphorus and adverse outcome in CKD stages 3 and 4. Notably, some but not all series suggest that the risk is significantly increased even for serum levels within the reference range of normality for serum phosphorus. The use of phosphate binders as a tool for controlling hyperphosphatemia has also been associated in observational studies with a better survival both in CKD and ESRD. However, no randomized clinical trial (RCT) has ever tested the impact of phosphate-lowering interventions (i.e., phosphate binder or nutritional intervention) on hard outcomes. Furthermore, a recent RCT seems to caution against the indiscriminate use of phosphate binders in CKD patients not receiving maintenance dialysis. Considering the clinical sequelae associated with phosphate overload in CKD, phosphate-lowering therapy is perceived as crucial and safe to prevent chronic kidney disease-mineral bone disorder (CKD-MBD). However, when to start in the course of CKD, how to monitor and whether to choose a calcium-based or a calcium-free phosphate binder are still subject to debate. Further research is deemed necessary to elucidate whether early treatment with phosphate binders is safe and may attenuate the CKD-MBD progression through phosphate load reduction.