The red cell membrane Li⁺/Na⁺exchange is a heteroexchange that operates in either direction across the cell membrane. It binds either Li⁺ or Na⁺ on one side of the membrane and it exchanges the transported species for either Li⁺ or Na⁺ on the opposite side in a stoichiometric ratio of 1:1. In the population, Li⁺/Na⁺exchange is unimodally distributed but skewed to the right. Such distribution results from superimposition of two normal distributions. Many laboratories have shown that red-cell Li⁺/Na⁺ exchange is increased in patients with essential hypertension, compared with normotensive controls. Among the various alterations of cell membrane cation transport reported in hypertension, the increase of red-cell Li⁺/Na⁺ exchange has been most widely investigated and confirmed. Moreover, increased Li⁺/Na⁺ exchange has been found in some clinical conditions related to hypertension, such as overweight and diabetes. Among diabetic patients, Li⁺/Na⁺ exchange is particularly high in patients with nephropathy, hypertension, and microalbuminuria, leading to the hypothesis that it can be considered a cellular marker of the risk of developing diabetic nephropathy. Furthermore, it is associated with severe and drug-resistant hypertension, insulin resistance, vascular and cardiac hypertrophy, hyperlipidemia, obesity, family history of hypertension, and of major cardiovascular accidents suggesting that high Li⁺/Na⁺ exchange could be a biochemical marker for increased cardiovascular risk. Regardless of its the pathophysiological significance, its measurement could be of clinical use as an intermediate phenotype of increased cardiovascular risk.