Considerable progress has been made toward understanding the mechanisms of intracellular pH (pHi) regulation since the last comprehensive reviews appeared (96,364,454). This new understanding is principally the result of new techniques that permit the measurement of transient changes in pHi. Perhaps the most fruitful among these methods has been the application of pH-sensitive microelectrodes. Nuclear magnetic resonance spectroscopy and spectrophotometry have also contributed to the advance of our knowledge and hold even greater promise for the futu. re. In addition progress has been made with older techniques, particularly. the weak acid and base methods. Normal pHi values have been established for a wide variety of preparations. New insights have been gained into the effect on pHi of permeation by the neutral and ionized forms of weak acids and bases. Studies of the temperature dependence of pHi have been extended, and the controversy over the supposed equilibrium distribution of H+ has been laid to rest. Considerable attention has been paid to the careful definition and measurement of intracellular buffering power. Studies on the internal pH of organelles have intensified. Finally, the implications of pHi regulation for phenomena ranging from muscle tension to epithelial acid secretion are becoming more appreciated. The purpose of this review is to critically exam. ine these recent adv ‘antes (with particular emphasis on results obtained with microelectrodes), to analyze older work in the light of recent progress, and to provide an historical perspective whenever appropriate. Previous comprehensive reviews include Caldwell’s classic PaPer (74) and the more recent efforts of Robson et al.(364), Waddell and Bates (454), and Cohen and Iles (96). Walker and Brown’s review (459) on intracellular ion activities contains a section on measurements of pHi with microelectrodes. Short reviews of limited scope have been written by Siesjo (406), Sorokina (419), Hinke and Menard (189), De Weer (116), Thomas (433), Roos (369), Boron (38, 39), and Gillies and Deamer (145, 146).