Since phosphorus plays a critical role in diverse biological processes, regulation of the phosphorus balance and homeostasis are critical to the well-being of the organism. Recent findings point to the presence of a phosphate-sensing mechanism in the various organs and the presence of novel intestinal effectors that alter the renal phosphate excretion after the ingestion of a phosphate-containing meal. Recent studies have provided strong evidence that the sodium-phosphate cotransporter NaPi-IIb is responsible for sodium-dependent phosphate absorption by the small intestine, and this protein might link changes in dietary phosphate to altered renal phosphate excretion in order to maintain the phosphate balance. It has been established that different regions of the small intestine respond differently to acute or chronic changes in dietary phosphate load and that phosphatonins inhibit both renal and intestinal phosphate transport.