Using a classical candidate gene approach, we have described a common C825T polymorphism in the gene GNB3, encoding the ubiquitously expressed β3 subunit of heterotrimeric G proteins. The 825T allele causes alternative splicing of the gene and the generation of a truncated but functionally active splice variant of Gβ3, referred to as Gβ3s. In addition, the presence of a 825T allele is predictive of an enhanced signal transduction via PTX-sensitive G proteins. Caucasian carriers of the 825T allele show a significantly increased risk for hypertension, most likely “low renin hypertension”, and show an increased response to thiazide diuretics. The 825T allele comes along with an increased renal perfusion and accumulates significantly in the individuals with a strong family history of hypertension. Highest frequencies of the 825T allele (up to 80%) are found in “old” ethnicities, e.g. black Africans, African Americans, bushmen, and Australian aborigines. This suggests that enhanced G protein activation represents a thrifty genotype which might have facilitated survival in our ancestors. Frequencies of the 825T allele are significant lower in Asians (approximately 40 to 50%) and Caucasians (30%). More recent studies show that young 825T allele carriers are predisposed for obesity and this association could be confirmed across different ethnicities including young Germans, as well as Chinese and black African individuals. Moreover, there is some evidence for an association with type-2 diabetes and cardiovascular disease. Genotyping at the GNB3 locus may represent an interesting candidate in a preventive medicine because individuals at risk for obesity and hypertension can be identified early and then can counteract their genetic predisposition through changes in lifestyle.