Abstract: New approaches to assessing the role of the kidneys in water–salt homeostasis in humans have been proposed. The roles of the kidneys in the continuous restoration of the ideal composition and volume of fluids of the internal environment, the formation of the protein composition of blood serum, its oncotic pressure for maintaining the volumes of intra- and extravascular fluid are considered. The significance and endocrine mechanisms of regulation of fluid reabsorption in the proximal segment of the nephron have been shown. The role of the kidneys in maintaining the endocrine status of the blood has been analyzed. The functional and diagnostic value of not only the absolute concentration of sodium and potassium ions in the blood serum, but also their ratio has been proven. The idea of the importance of the cascade system of regulation of water–salt balance in the body in mitigating drastic shifts in the physicochemical parameters of fluids in the internal environment during water and food consumption has been formulated. The problem of the functional organization of sensory support of blood physicochemical parameters (osmoregulation etc.) is discussed. An approach has been found for the use of clearance equations to assess the role of the kidneys in cell volume regulation as one of the most significant physiological parameters. The problem of the specificity of the physiology of the kidney and water–salt homeostasis in humans is analyzed.