The individual variation in the efficacy of and tolerability to antihypertensive drugs in human essential hypertension is linked to the genetic heterogeneity of this multifactorial disease. Different approaches have been pursued in the attempt to correlate a specific responsiveness to the therapy with some phenotypic traits of the patients, such as the renin-angiotensin profile or the characteristics of cell ion transports. More recently, a 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 in both animal models and patients. Also, individual variation to therapy can now be studied from the genetic point of view using pharmacogenomics, that is, the study of the genes or loci which are involved in determining the responsiveness to a given drug. Only a few examples of this approach are available to date. Our group has identified a polymorphism of the genes for the cytoskeletal protein, adducin, which is linked to both rat and human hypertension, sodium sensitivity and to the pressor responsiveness to diuretic therapy. These results, together with the indication that adducin can play a functional role by modulating the cellular sodium transport, have led to the identification of a new antihypertensive compound, which could be a candidate for the selective treatment of those patients in whom alterations of the renal sodium handling are associated with specific genetic traits such as the polymorphism for adducin.