Background: The genetic complexity of arterial hypertension hampers the approaches aimed at establishing the clinical impact of SNPs either in candidate genes or loci detected with GWAS. The combination of genotyping of these genes with the inhibition of their function with a selective drug may overcome their complexity and help in defining the right drug for the right patient. Cellular effects of human mutated adducin and endogenous ouabain (EO) on the Na-K pump are selectively inhibited by rostafuroxin at sub nanomolar concentrations. Objective: Here we evaluated whether the alleles of genes (ADD1/3, LSS, HSD3B1/2 and MDR1) involved in EO metabolism and adducin-rostafuroxin effects influence the blood pressure response of these drugs in new discovered and never treated patients. Design and Methods: Patients are classified as responder (R) or non responder (NR) according to the first tertile of SBP variation (primary end-point) after 1 month therapy. Results: The antihypertensive activity of nanomoles oral doses of rostafuroxin, but not the other commonly used antihypertensives losartan or hydrochlorothiazide, was predicted by combinations of the above gene variants; BP fell -16.2 ± 1.2 mmHg in patients with and -2.5 ± 1.2 mmHg without this gene profile (p = 9*10–8). Furthermore, this genetic profile discriminates R patients with a sensitivity of 52%, a specificity of 89% and an Odd Ratio to be responder of 8.9 in rostafuroxin patients only. Conclusions: The combination of genetics with selective targeting of specific mechanism(s) can overcome contemporary limitations of the genetic complexity of human hypertension and provide a specific therapy for 23% of patients.