Sodium ion has been traditionally conceived to be the main effector of changes in cellular volumes. Active extrusion of sodium by the Na/K pumps is considered to counterbalance the oncotic pressure of intracellular macromolecules. Development of NMR techniques for non-invasive measurement of cellular sodium and water contents has yielded new insights into cell volume regulation. The "indirect sodium-water coupling" hypothesis postulates that sodium correlates closely to changes in intracellular volume due to its extensive coupling with the transport of osmotically-active ions and molecules. Intracellular sodium and water contents change in parallel, however the coefficients that relate their trans-membranal fluxes in cardiac muscle vary widely. In limited cases, sodium-water uncoupling was observed upon attenuation of intracellular calcium and energy metabolism. This hypothesis offers an alternative mechanistic explanation that underlines the importance of additional volume-regulatory mechanisms bwsides sodium homeostasis.