Of the abnormalities of cation transport described in human essential hypertension, an increased maximal activity for red blood cell lithium-sodium (RBC Li(+)-Na+) countertransport is the most appealing candidate for a genetically mediated marker for risk of future hypertension. Population studies have demonstrated that the distribution of values for countertransport can be modelled statistically as a mixture of two overlapping subpopulations. These two modes could result from the action of a single principal determinant, and pedigree-based studies of the genetic transmission of RBC Li(+)-Na+ intertransport activity have suggested that factor may represent the effect of a major monogenic influence segregating in a Mendelian recessive fashion. Although the molecular nature of the proposed genetic lesion underlying high RBC Li(+)-Na+ countertransport is not yet known, a recent linkage study suggests it may be localized to chromosome 4. A preliminary report of a prospective analysis of the predictive value of high RBC Li(+)-Na+ countertransport for future hypertension supports its utility as a premorbid marker for genetic risk of future hypertension. Allelic differences at a genetic locus controlling RBC Li(+)-Na+ countertransport activity may contribute directly to interdividual blood pressure differences or may be linked to other genes that do.