The effect of sodium in human blood pressure has been a contentious subject of considerable debate for decades. Nonetheless, it is generally conceded that there is heterogeneity to alterations in sodium and extracellular fluid volume in the blood pressure responses of normal and hypertensive humans. Although there are many forms of experimental and clinical hypertension that are clearly related to abnormalities of sodium handling and metabolism, it has been only the advent of the genetic revolution that has provided critical new insight into the mechanisms involved in many of these conditions. In this review, the clinical manifestations of salt sensitivity and several clinical syndromes associated with abnormal sodium metabolism are discussed, and factors that appear to be involved in many of the clinical abnormalities as well as relevant new insights derived from basic research are elucidated.