Acute hyponatremia can cause death if cerebral edema is not treated promptly. Conversely, if chronic hyponatremia is corrected too rapidly, osmotic demyelination may ensue, which also potentially is lethal. However, these severe complications of hyponatremia are relatively uncommon and often preventable. More commonly, hyponatremia predicts mortality in patients with advanced heart failure or liver cirrhosis. In these conditions, it generally is assumed that hyponatremia reflects the severity of the underlying disease rather than contributing directly to mortality. The same assumption holds for the recently reported associations between hyponatremia and mortality in patients with pulmonary embolism, pulmonary hypertension, pneumonia, and myocardial infarction. However, recent data suggest that chronic and mild hyponatremia in the general population also are associated with mortality. In addition, hyponatremia has been associated with mortality in long-term hemodialysis patients without residual function in whom the underlying disease cannot be responsible for hyponatremia. These new data raise the question of whether hyponatremia by itself can contribute to mortality or it remains a surrogate marker for other unknown risk factors. We review hyponatremia and mortality and explore the possibility that hyponatremia perturbs normal physiology in the absence of cerebral edema or osmotic demyelination. Am J Kidney Dis. 62(1):139-149. (C) 2013 by the National Kidney Foundation, Inc.