An effort is made to explain the salt loading of hypertonicity-treated human red blood cells (RBC) and their post-hypertonic lysis, which occurs upon resuspension to isotonic media. It is recognized that the salt loading is consistent with the regulatory volume increase response - a physiological response applied by cells to adapt to hypertonic conditions. It is therefore hypothesized that salt loading occurs via physiological ion transport pathways, allowing passive dissipative fluxes across the plasma membrane with the preservation of membrane integrity. It is argued that post-hypertonic lysis is essentially a hypotonic lysis occurring already in an isotonic medium due to the excess salt in the cytoplasm. A simplified physiological model accounting for transmembrane ion fluxes was applied to simulate the RBC physiological state to address the problem quantitatively. Instead of assuming the plasma membrane to be impermeable to ions, the dynamic nature of cell physiological state and capacity of cells to perform acute cell volume regulation by increasing passive cation plasma membrane permeability is recognized. It is shown that the RBC plasma membrane contains ion pathways capable of supporting a several-order increase in catio permeability, facilitating overall salt loading. The obtained picture, consistent with general physiology, predicts the experimentally observed RBC behavior. Although treated in theory, evidence supporting the proposed theory is provided, and the high explanatory power of the proposed idea is demonstrated. While focused on human RBCs, this study offers a general mechanism for the osmotic injury of cells exposed to hypertonic solutions - conditions relevant to cell cryopreservation - since many cells possess cell volume regulation mechanisms. Implications of the proposed hypothesis explaining the cryoprotective mechanism of common cryoprotectants are discussed, and additives targeting ion transport pathways are suggested as novel cryoprotectants.