Inorganic phosphate homeostasis is controlled by a complex network of regulatory mechanisms. This complexity is not only the consequence of the physiological relevance of Pi, but also of the narrow threshold that separates physiological from toxic concentrations of phosphate in blood. Pi is involved in bone formation, pH control, high-energy bonds, signal transduction, membrane and nucleic acid composition, etc., but when homeostasis is lost (e.g. during chronic kidney disease), hyperphosphatemia emerges with dramatic consequences, such as Mönckeberg’s sclerosis, calciphylaxis or secondary hyperparathyroidism. To avoid it, under physiological conditions the rate of Pi ingestion should equal approximately the rate of Pi excretion. All mechanisms that have been described to date as regulators of Pi homeostasis end up with a control of the abundance of Pi transporters in the plasma membrane, mostly of epithelial cells. These mechanisms can be either a fast (acute, within minutes-hours) or slow (chronic, days) response, and in both cases they are of either hormonal and non-hormonal nature. Acute mechanisms of control only occur in the kidney, and they involve the insertion to or retrieval (endocytosis) from the cell membrane of existing Na-coupled Pi transporters. Chronic mechanisms involve the synthesis of new Pi transporters through transcriptional or posttranscriptional mechanisms. Changes of dietary Pi as well as parathyroid hormone and phosphatonins (eg. FGF23) act both as acute and chronic regulators, while vitamin D3, thyroid hormone, insulin and glucocorticoids are only chronic regulators. The kidney controls Pi blood concentration through changes in the rates of Pi excretion/reabsorption. Therefore, the kidney is the target for most acute and chronic regulators, which are acting on the proximal tubular epithelial cells of the nephrons. These cells express at least four different Na-coupled Pi transporters belonging to the type II (SLC34; NaPi-IIa and NaPi-IIc), and to the type III (SLC20; Pit-1 and Pit-2) families of transporters. Of these , NaPi-IIa is sufficient to handle >90% of all reabsorbed Pi in the proximal tubule; the roles of the other three transporters are unclear. With respect to changes in dietary Pi, for example, the kidney has a fundamental role of avoiding dangerous increases of Pi in blood. When a high Pi containing diet is ingested, the kidney increases Pi excretion well before the concentration of phosphate in blood is raised. In addition, the proximal tubular epithelial cells also exhibit an autonomous mechanism to sense the concentration of Pi in the lumen of the proximal tubule (or the culture media). Both mechanisms of sensing Pi concentration ensure that the control of Pi concentration in blood is maintained, independently of the source of phosphate (i.e. of dietary or internal origin, such as bone turnover). The intestine has been classically described as an organ simply involved in Pi absorption with only modest implications in chronic control of Pi homeostasis. Recent advances, however, are uncovering new functions, including a role as sensor of Pi concentration in the diet. Evidence now suggests that the intestine senses Pi but also signals it to the kidney, to adapt the rate of Pi excretion to the Pi concentration of the meal. This role is of critical importance to avoid increases of Pi in the blood that could be the cause of undesirable intravascular calcium-phosphate precipitation. New intestinal phosphatonin candidates, such as MEPE, could be involved in the signalling process. The molecular identification of the intestinal Pi sensor is, at present, a major challenge in Pi homeostasis research. Finally, not only the signalling viewpoint, but also the mechanisms of Pi intestinal absorption are now being elucidated. Pi intestinal absorption can be divided into transport and paracellular routes, and the proportion involved in each route most likely depends on the concentration of Pi in the lumen. The transport component seems to be the result of the activity of three Na-coupled transporters, NaPi-IIb, Pit-1 and Pit-2, and the relative involvement of each of them is also unclear. All of them are high affinity Pi transporters, with very low apparent Km values compared to the usual Pi concentrations in lumen. Regional expression of the transporters is non-homogeneous. For example, NaPi-IIb is mostly expressed in duodenum and jejunum in rat, but this abundance pattern is altered by changes in dietary Pi content, especially during Pi deprivation. In conclusion, our present understanding Pi homeostasis control is far from clear, and recent discoveries are increasing the complexity picture of the mechanisms involved. The coordinated interplay of Pi concentration sensing mechanisms, phosphatonins and other components need to be clarified. Similarly, the precise role of the different Pi transporters in phosphate handling and homeostasis has to be understood, especially in the case of type III transporters, Pit-1 and Pit-2. Presumably, these challenges are going to provide exciting activities and outcomes during the next years.