In spite of a large body of physiological, biochemical, and recently genetic investigations, the causes of hypertension remain largely unknown. Recognition that hypertension is, in part, genetically determined has motivated studies to identify mutations conferring susceptibility. To date, mutations in at least 10 genes have been shown to alter blood pressure. The majority are rare mutations responsible for various mendelian hyper- and hypotensive syndromes, imparting large quantitative effects. Those causing hypertension are glucocorticoid-remediable aldosteronism, the syndrome of apparent mineralocorticoid excess, and Liddle's syndrome. Conversely, pseudohypoaldosteronism type 1, Bartter's, and Gitelman's syndromes all cause hypotension. In addition, mutations in the angiotensinogen gene are associated with hypertension. All these mutations alter blood pressure through a common pathway, affecting salt and water reabsorption in the kidney. These findings demonstrate the place of molecular genetic approaches in elucidating the underlying determinants of human blood pressure variation and may provide insight into the physiological mechanisms underlying common forms of hypertension.