The H(+) concentration in human blood is kept within very narrow limits, ~40 nmol/L, despite the fact that dietary metabolism generates acid and base loads that are added to the systemic circulation throughout the life of mammals. One of the primary functions of the kidney is to maintain the constancy of systemic acid-base chemistry. The kidney has evolved the capacity to regulate blood acidity by performing three key functions: (i) reabsorb HCO3(-) that is filtered through the glomeruli to prevent its excretion in the urine; (ii) generate a sufficient quantity of new HCO3(-) to compensate for the loss of HCO3(-) resulting from dietary metabolic H(+) loads and loss of HCO3(-) in the urea cycle; and (iii) excrete HCO3(-) (or metabolizable organic anions) following a systemic base load. The ability of the kidney to perform these functions requires that various cell types throughout the nephron respond to changes in acid-base chemistry by modulating specific ion transport and/or metabolic processes in a coordinated fashion such that the urine and renal vein chemistry is altered appropriately. The purpose of the article is to provide the interested reader with a broad review of a field that began historically ~60 years ago with whole animal studies, and has evolved to where we are currently addressing questions related to kidney acid-base regulation at the single protein structure/function level.