Sodium chloride is the most abundant salt in extracellular fluid. In normal individuals, the tonicity exerted by dissolved sodium chloride determines plasma osmolality and indirectly determines intracellular tonicity and cell volume. Uremic patients retain nitrogenous wastes and have an elevated plasma osmolality. While urea exhibits osmotic activity in serum, no sustained gradient can be established across cell boundaries because it readily diffuses through cell membranes. Thus, sodium remains the major indicator of body tonicity and determines the distribution of water across the intracellular-extracellular boundary, subsequent cell volume, thirst, and, among patients with renal insufficiency, systemic blood pressure. As a result of highly conserved plasma tonicity control systems, uremic subjects demonstrate remarkable stability of their serum sodium. Dialysate is a synthetic interstitial fluid capable of reconstituting extracellular fluid composition through urea extraction and extremely efficient solute and solvent (salt and water) transfer to the patient. Subtle transdialyzer gradients deliver and remove large quantities of trace elements, solvent, and solute to patients, creating a variety of dialysis "disequilibrium" syndromes manifest as cellular and systemic distress. Every dialysis patient uses dialysate, and the most abundant chemicals in dialysate are salt and water. Despite its universal use, no consensus on dialysate composition or tonicity exists. This can only be explained if we believe that dialysate composition is best determined by matching unique dialysis delivery system characteristics to specific patient requirements. Such a paradigm treats dialysate as a drug and the dialysis system as a delivery device. Understanding the therapeutic and toxic profiles of this drug (dialysate) and its delivery device (the dialyzer) is important to safe, effective, goal-directed modifications of therapy. This article explores some of the historical rationale behind choosing specific dialysate tonicities.