Although progress in the genetics of essential hypertension may seem disappointing, it has considerable potential in defining research directions that will ultimately translate into clinical practice. The hypothesis that genetic variation at the angiotensinogen locus impacts on individual susceptibility to develop essential hypertension has motivated a substantial body of research by us and many others. We examine how analyses of the mechanisms by which variation in angiotensinogen expression may contribute to disease susceptibility and may have arisen in human populations have progressed in recent years. Although the objective of personalized medicine is still in the future, a genetic hypothesis based on human variation can uniquely empower functional genomics approaches to reach such an ultimate goal.