: The management of hyperphosphatemia in patients with chronic kidney disease (CKD) is complicated, requiring a multidisciplinary approach that includes dietary phosphate restriction, dialysis, and phosphate binders.: We describe key players involved in regulating inorganic phosphate homeostasis and their differential role in healthy people and different stages of CKD. The contribution of paracellular and transcellular intestinal absorptive mechanisms are also examined. Finally, we illuminate recent therapeutic approaches for hyperphosphatemia in CKD. We searched PubMed/Medline (up to November 2019) using the following terms: chronic kidney disease, dialysis, diet, hyperphosphatemia, NaPi2b, nicotinamide, phosphate binder, secondary hyperparathyroidism, tenapanor and vascular calcification.: The precise mechanisms regulating intestinal phosphate absorption in humans is not completely understood. However, it is now established that this process involves two independent pathways: a) active transport (i.e. transcellular route, via specific ion transporters) and inactive transport (i.e. paracellular route across tight junctions). Dietary phosphate restriction and phosphate-binder use can lead to an undesirable maladaptive increase in phosphate uptake and promote active phosphate transport by increased expression of the gastrointestinal sodium-dependent phosphate transporter, NaPi2b. Nicotinamide may overcome these limitations through the inhibition of NaPi2b, by improved efficacy and reduced phosphate binder use and better compliance.