To write about the “Physiological Basis for the Action of Newer Diuretic Agents” in the format of a review article at this time leaves one with something less than a sense of satisfaction. This reservation has not been because of any lack of progress in this area of research. Rather, it is the sense of certainty that the vibrant interest in this field of research may be projected to evoke newer knowledge so rapidly as to render this account immediately incomplete in scope and inadequate in detail. Nevertheless, many of the generalizations to be presented herein need to be made and should be accumulated in one place, for information, for appraisal and for further inquiry. Recent advances in renal physiology have been important and exciting. Research on the pharmacology of diuretic agents has never been more active than in the past few years. There has been a number of excellent reviews of the important developments in renal electrolyte physiology, especially over the past dozen or so years(20, 82, 95, 256, 257, 273, 303). Likewise, the descriptive pharmacology of diuretic agents has been reviewed more or less comprehensively recently(26, 27, 29, 104, 159, 161, 214, 218, 239, 272). Of these, the recent review by Beyer and Baer (29) is in a sense a companion to this article, for it considers the pharmacology of the several categories of diuretic agents in a descriptive manner rather than with the functional approach attempted herein. It is the purpose of this review to consider the more recent advances in the renal modulation of electrolyte and water balance in terms of the pharmacology of the newer agents that have been designed to fulfill that therapeutic objective. At the risk of erring in detail and concept, we have attempted herein to consider how the physiological disposition of drugs, particularly chlorothiazide and its congeners, influences their effect on salt and water elimination. We have drawn on certain as yet unpublished work from this laboratory where it has seemed appropriate and convenient to do so. No attempt has been made to cover comprehensively the voluminous literature in this field, nor has reference been made to the considerable utility of these agents beyond their nephrotropic attributes.