The G-protein beta3 subunit (GNB3) C825T polymorphism was detected through a classical candidate gene approach using cell lines with enhanced G-protein activation from patients with essential hypertension. The 825T allele is associated with the expression of a shortened, functionally active splice variant of the G-protein beta3 subunit and enhanced intracellular signal transduction. Independent studies have confirmed an association of the 825T allele with hypertension in whites. Potential pathogenetic mechanisms comprise an increased susceptibility for obesity in 825T allele carriers and, potentially, increased responsiveness to vasoactive hormones. Both phenomena appear to be strongly influenced by lifestyle in the sense of a gene-environment interaction. Whether hypertensive 825T allele carriers are at increased risk for stroke and left ventricular hypertrophy remains controversial. Current studies try to define optimal therapy strategies for hypertensive 825T allele carriers.