Rare mutations in genes affecting renal salt handling cause various syndromes of hypotension and hypertension and have produced important insights into major physiological processes and their regulation. However, the question arises whether these mutations may also affect blood pressure in a more general population and may contribute to the complex control of arterial blood pressure. The group of R. Lifton has demonstrated in a large cohort from the Framingham Heart Study that inactivating mutations in several proteins mediating renal salt reabsorption in the heterozygous state are associated with significantly lower blood pressure. The frequency of such alleles may be much higher in the general population than previously anticipated and may explain at least in part the complex genetics of human hypertension.