The kidney fulfils a central role in maintaining and controlling systemic acid-base homeostasis. Three major mechanisms are operative: 1) reabsorption of filtered bicarbonate, mostly achieved by the proximal tubule, 2) ammoniagenesis in the proximal tubule regenerating bicarbonate used to buffer protons from metabolism and generating ammonium ions for renal acid excretion, 3) active secretion of protons and de novo generation of bicarbonate along the collecting duct. This talk will focus on the latter two processes highlighting mechanisms in the proximal tubule contributing to ammoniagenesis and transport pathways in the collecting duct that mediate ammonia and proton excretion. Ammoniagenesis in the proximal tubule requires glutamine as substrate. Glutamine import into the cells of the proximal tubule is mostly mediated by the basolateral SNAT3 amino acid transporter, glutamine is then taken up by mitochondria and metabolized to yield ammonium and bicarbonate. The import of glutamine and its subsequent metabolism is highly regulated and stimulated by acidosis in a coordinated manner involving SNAT3 and the subsequent enzymes PDG, GDH, PEPCK and components of the Krebs cycle and gluconeogenic pathway. A mouse model lacking SNAT3 shows reduced urinary ammonium excretion and mice die around 20 days after birth. Final excretion of ammonia into urine is achieved by the cells lining the collecting duct. There, ammonia and protons are secreted in parallel. We have shown that the rhesus protein RhCG is expressed on basolateral and luminal membranes of these cells and that genetic ablation of RhCG in mice impairs urinary ammonium excretion. On the cellular level, microperfusion experiments of isolated collecting ducts demonstrated that RhCG mediates NH3 but not NH4+ transport and is the limiting step on the luminal membrane. On the basolateral side, RhCG contributes to NH3 uptake but other pathways for NH3 and NH4+ exist. NH3 in urine is trapped after titration to NH4+. Protons are excreted by the action of H+-ATPases, multisubunit pumps that are highly regulated by many factors including acid-base status and the renin-angiotensin-aldosterone system. Interestingly, one accessory protein of the pump serves also as receptor for (pro)renin. Mutations in the B1 and a4 H+-ATPase subunits cause distal renal tubular acidosis in humans. Similarly, mice lacking the B1 subunit have a reduced ability to acidify urine while the B2 isoform compensates partially for the loss of B1. However, not all functions of B1 are compensated and a trafficking defect of pumps lacking the B1 subunit is observed. Newly generated bicarbonate in the collecting duct is released by the AE1 anion exchanger mediating exchange of bicarbonate or extracellular chloride. Mutations in this exchanger have been detected in patients with autosomal dominant forms of distal renal tubular acidosis. The absence of this transporter apparently affects not only the transport capacity of intercalated cells but also their differentiation as evident from AE1 KO mice and kidney biopsies from patients. A further important aspect of renal acid excretion along the collecting duct is the adaptive remodelling of the cellular profile of the collecting duct in response to alterations of systemic acid-base balance. A higher systemic acid load causes an increase in the (relative) abundance of acid secretory type A intercalated cells whereas a higher alkali load reverses this process and enhances the (relative) number of type B bicarbonate secretory cells. Stimulation of latter cells may also occur with changes in chloride balance linking functionally acid-base and chloride (salt) homeostasis. The change in intercalated cell subtypes may be via interconversion of functional subtypes or may also involve regulated proliferation of differentiated intercalated cells as suggested by immunohistochemistry identifying differentiated type A or B intercalated cells with various markers of active DNA synthesis and cell proliferation. How this process is regulated remains elusive to date but may involve hormones and factors involved in mediating the stimulation of renal acid excretion during acid loads.