Recent theoretical considerations have played an important role in advancing our understanding of the physiological mechanisms responsible for perturbing the plasma water sodium concentration ([Na(+)](pw)) in health and disease. Central to these considerations is the original empirical relationship between the [Na(+)](pw) and total exchangeable sodium (Na(e)), total exchangeable potassium (K(e)), and total body water (TBW) initially discovered by Edelman and colleagues (Edelman IS, Leibman J, O'Meara MP, and Birkenfeld LW. J Clin Invest 37: 1236-1256, 1958). The non-zero values of the slope and y-intercept in the Edelman equation are a consequence of the effects of the osmotic coefficient of Na(+) salts at physiological concentrations and Gibbs-Donnan and osmotic equilibrium. Moreover, in addition to Na(e), K(e), and TBW, the physiological components of the y-intercept in this equation play a role in modulating the [Na(+)](pw) and in the generation of the dysnatremias. In this review, the pathophysiological mechanisms underlying the generation and treatment of the dysnatremias are analyzed theoretically and quantitatively. Importantly, the non-zero values of both the slope and y-intercept in the Edelman equation result in several theoretical predictions that can be tested experimentally and have been mathematically incorporated into recently derived equations used to analyze both the generation and the optimal treatment of the dysnatremias. In addition, we review current concepts regarding 1) the role of Gibbs-Donnan and osmotic equilibrium in the determination of the [Na(+)](pw); 2) the modulating effect of osmotically inactive exchangeable Na(+) and K(+) on the [Na(+)](pw); 3) the effect of glucose on the [Na(+)](pw) as reflected by changes in Na(e), K(e), and TBW as well as changes in several components of the y-intercept resulting from the hyperglycemia; and 4) the complex role of K(+) in modulating the [Na(+)](pw).