Through their action on the distal nephron, diuretics may produce systemic acid-base disturbances: metabolic alkalosis with thiazides or loop diuretics, and metabolic acidosis with amiloride. Enhanced acid excretion may be due to a local effect on the diuretic target cell (a shift of Na⁺ reabsorption from NaCl transport to Na⁺/H⁺ exchange), or an effect at a distance, namely increases in luminal fluid flow or luminal Na⁺ concentration may enhance more distal proton secretion. Both local and distance effects are supported by micropuncture data. In the present work, mathematical models of distal convoluted tubule (DCT)/connecting tubule (CNT) (Weinstein, Am. J. Physiol. 289:F721-F741, 2005b), and cortical and medullary collecting ducts (CD) (Weinstein, Am. J. Physiol. 283:F1237-F1251, 2002a) have been concatenated to yield a model of rat distal nephron (DN). Among the segments of this distal nephron, the DCT-CNT is responsible for the major portion of distal acidification. Predictions from the model calculations include: (1) With increasing distal Na⁺ delivery, there is little change in net acid excretion, but a shift in acidification locus from shared DCT and CNT contributions, to DCT prominence. (2) Urinary acidification by thiazides is primarily local (in DCT) via the shift in Na⁺ reabsorption from NaCl cotransport to entry via NHE2. Increased NaCl delivery to CNT increases beta cell HCO3 secretion, and thus blunts urine acidification. (3) In contrast to conclusions drawn from the isolated CD model, inclusion of CNT now reproduces the observed distal acidification defect found with ENaC block, so that this action of amiloride appears to be sufficient to produce "voltage-dependent" distal renal tubular acidosis. (4) The effect of furosemide to enhance distal urinary acidification is not reproduced by the model without major up-regulation of CNT alpha cell transport, perhaps as a result of increased luminal flow.