Renal and hepatic nitrogen metabolism are linked by an interorgan glutamine flux, coupling both renal ammoniagenesis and hepatic urea production to systemic acid-base regulation. Reconsideration of established pathways and recent observations led to a conceptional change with a movement from a two-organ concept (lungs and kidney) of acid-base balance to a three-or-more organ concept (lungs, kidney, liver). This development implies new regulatory sites of systemic pH control and consequently a new pathophysiological understanding of derangements of acid-base homeostasis. In this new concept the urea cycle regulates the removal of metabolically generated bicarbonate during a protein load in a pH- and bicarbonate-dependent manner. This is related to a switch of hepatic ammonium detoxication from urea to glutamine synthesis in metabolic acidosis, and vice versa in alkalosis. An adaptive increase in the renal capacity for glutamine deamidation and deamination and for ammonium excretion leads to a proportional decrease in renal urea excretion at the expense of ammonium in acidotic conditions. The present review summarizes experimental data and clinical implications resulting from this new concept, which was also the subject of a recent Conference of the German Society for Clinical Chemistry "Mechanisms and Control of pH Homeostasis".