In central osmoregulation, a 1-2% rise in plasma osmolality is detected by specialized osmoreceptors located in the circumventricular organs of the hypothalamus. A disturbance in this tightly regulated balance will result in either hyponatremia or hypernatremia, which are both common electrolyte disorders in hospitalized patients. Despite the high clinical importance of hypo- and hypernatremia and the fact that this vital process has been studied for many years, the genes and corresponding proteins involved in this process are just beginning to be identified. To identify novel genes involved in the (patho-)physiology of osmoregulation, we therefore employed haplotype association mapping on an aging group of 27 inbred mouse strains. Serum sodium concentrations were determined in all strains at 6, 12, and 18 mo of age, and high-resolution mapping was performed for males and females separately. We identified a total of five loci associated with the serum sodium concentration of which the locus on chromosome 14, containing only one known gene (Nalcn), showed the strongest correlation. Within this locus three different haplotypes could be distinguished, which associated with different average serum sodium levels. The association of Nalcn with sodium levels was confirmed by analysis of heterozygous Nalcn knockout mice, which displayed hypernatremia compared with wild-type littermates. Our study demonstrates that Nalcn associates with serum sodium concentrations in mice and indicates that Nalcn is an important novel player in osmoregulation.