A number of recent reviews have addressed the issue of the pharmacogenomics of primary hypertension and related complications by considering the data on the genotype-drug response relationship. Here we mainly discuss the methodological aspects of this issue, trying to integrate 'traditional' clinical and experimental pathophysiology and therapy-pharmacology with the 'new' genetics. Such integration is indispensable to: a). define the appropriate 'context' (genetic background, environment, age, gender, phase of hypertension, previous therapy etc.) in which a given genotype-drug response relationship should be tested (it is indeed likely that many discrepancies among published data originate from context's interference); b). assign the correct clinical meaning to the results obtained by statistics and functional genetics methodologies; c). define a novel clinical entity caused by a disease favoring allele, alone or in combination with other alleles, with a consistent clinical picture, prognosis and responsiveness to the appropriate drug; d). estimate the size of the population target amenable to benefit from a therapeutic intervention developed according to the pharmacogenomics' principles; e). develop a novel drug that selectively interferes with the sequence of events triggered by the genetic mechanism(s) underlying the clinical entity. Peculiar to this strategy is to look for consistency among findings gathered from different 'contexts' after having properly accounted for the context's dependency of the results.