Despite several decades of research interest and productivity, many aspects of hyponatremia and hypo-osmolar disorders remain incompletely understood. Among these aspects are questions relating to the morbidity and mortality actually attributable to hyponatremia, possible hormonal and gender-associated risk factors underlying susceptibility to neurologic complications from hyponatremic encephalopathy, the stimuli to arginine vasopressin secretion in some atypical subsets of patients with the syndrome of inappropriate antidiuretic hormone secretion and other hyponatremic disorders, the contributions of natriuresis and natriuretic peptides to hyponatremic states, the pathologic determinants of brain demyelination that sometimes follow rapid correction of hyponatremia, and appropriate treatment guidelines for patients with acute and chronic hyponatremia. The recent literature confirms that acceptable answers to these questions and others are still not available, and a better understanding of basic issues regarding the pathophysiology of hyponatremia is needed. Several recent advances stand out as being likely to enhance our future understanding of hyponatremia and hypo-osmolar states. First are studies of cellular mechanisms of volume regulation in kidney and brain tissue in response to changes in osmolality. Many, though clearly not all, clinical observations can be better understood by considering them in the conceptual framework provided by knowledge of cell and body fluid compartment volume regulation. Second is the elucidation of several important protein structures via complementary DNA cloning, including the arginine vasopressin V^ and V2 receptors, several organic osmolyte transporters, and the CHIP28 water channel. Future application of these new tools to carefully designed and executed physiologic studies will likely add considerable new knowledge to our understanding of hyponatremia. Third is the development and increasing application of nuclear magnetic resonance spectroscopy and imaging methods that will allow more detailed analyses of acute changes in brain metabolism during hyponatremia and following correction. Finally, the recent development of nonpeptide antagonists to arginine vasopressin V^ and V2 receptors should enable clinical studies to assess more accurately the contribution of arginine vasopressin-induced antidiuresis to hyponatremia and more importantly holds the promise of more effective therapies for hyponatremic patients.