Identifying the genetic predictors of the therapeutic response to drugs is the role of pharmacogenomics. Although polymorphisms in several genes have been associated with the blood pressure response to diuretics, beta-blockers and ACE-inhibitors, the pharmacogenomics of essential hypertension is still attempting to find satisfactory scientific evidence to be translated into clinical practice. The main reasons for this apparent failure are: the small sample sizes of the cohorts of patients analyzed, the methodological variability, the complexity of the biological organization, the context-dependency and the genetic heterogeneity. This review will summarize the available data on antihypertensive drugs and the criteria used for study design and conduction, focusing on their strong points and limitations.