This review summarizes the newly discovered molecular mechanism of secretin‐stimulated urine HCO₃^– excretion and the role of cystic fibrosis transmembrane conductance regulator (CFTR) in renal HCO₃^– excretion. The secretin receptor is functionally expressed in the basolateral membrane of the HCO₃^–‐secreting β‐intercalated cells of the collecting duct. Here it activates a fast and efficient secretion of HCO₃^– into the urine serving to normalize metabolic alkalosis. The ability to acutely increase renal base excretion is entirely dependent on functional pendrin (SLC26A4) and CFTR, and both proteins localize to the apical membrane of the β‐intercalated cells. In cystic fibrosis mice and patients, this function is absent or markedly reduced. We discuss that the alkaline tide, namely the transient urine alkalinity after a meal, has now received a clear physiological explanation.