Management of hyperphosphatemia in patients with dialysis-dependent chronic kidney disease remains a major challenge, requiring a multifaceted approach that includes dietary phosphate restriction, dialysis, and phosphate binders. However, these treatments fail to meet serum phosphate targets in many patients, potentially further exacerbating the significant morbidity and mortality burden associated with the disease. Recent advances in our understanding of the mechanisms underlying phosphate homeostasis have shed new light on the issue and suggest that gastrointestinal transport proteins may be promising targets for new hyperphosphatemia treatments. Drugs that inhibit or downregulate these transport proteins, and thus reduce phosphate uptake from the gut, may overcome some of the limitations of existing phosphate-lowering strategies, such as interdialytic rises in serum phosphate levels, poor adherence to dietary and phosphate-binder regimens, and maladaptive responses that can increase gastrointestinal phosphate absorption. Here, we review the latest preclinical and clinical data for two candidates in this novel drug class: tenapanor, a small-molecule inhibitor of the sodium/hydrogen ion-exchanger isoform 3, and nicotinamide, an inhibitor of sodium–phosphate-2b cotransporters. We also discuss how potential synergies in their mechanisms of action suggest that coadministering phosphate binders with sodium–phosphate-2b cotransporter inhibitors may yield additive benefits over traditional phosphate-binder therapy.