A tailored or individualized antihypertensive therapy represents the new frontier for the treatment of essential hypertension and its organ complications. Indeed, individual variation in the efficacy and tolerability of antihypertensive drugs in human essential hypertension is currently experienced by all physicians and is linked to the genetic heterogeneity of this multifactorial disease. Different approaches have been pursued in the attempt to correlate specific responsiveness to the therapy with phenotypic traits of the patients, but with poor results. More recently, the genetic approach to the study of the mechanisms underlying hypertension has led to the identification of some quantitative trait loci or genes that influence blood pressure both in animal models and in patients. But the relevance of these polymorphisms for defining and classifying patients in terms of therapy responsiveness must be analyzed in a more complex context that takes into account the crucial aspects of environmental influences, stage of disease, previous treatments, efficacy, tolerance, and duration of the treatment. Only a few examples of a pharmacogenomic approach to hypertension therapy are now available. In particular, the association of different variants of ACE, angiotensinogen, and G-protein genes with the blood pressure response to drugs interfering with RAS or beta-adrenergic receptor has been studied. However, the results of these studies cannot be considered conclusive, since not all the criteria have been fully applied for proper assessment of an association between genetic polymorphism and drug response. Our group has identified a polymorphism of the genes coding for the cytoskeletal protein, adducin, which is associated with both rat and human hypertension, sodium sensitivity, and the antihypertensive effects of diuretics. A modification of the renal Na-KATPase leading to an increase of tubular sodium reabsorption seems to be the most likely underlying mechanism. A new antihypertensive compound has been developed that can correct the abnormality of the renal Na-KATPase and the blood pressure increase associated with adducin polymorphism in the rat. At present, the antihypertensive activity of this compound is under evaluation in patients with different adducin genotypes.