Genetic variables have a role in the development of primary hypertension, according to family studies. The shift from this phenomenologic-biometric to a molecular-genetic approach, however, is more challenging. The dissecting of the poligenic complex of hypertension is based on the premise that the individual genetic variations underpinning the ocular hypertension must be more common in hypertensive patients compared to controls and should cosegregate with hypertensive in families. In the so-called monogenic type of hypertension, the validity of these assumptions was convincingly established. However, because of the complex network of feedback mechanisms that regulate blood pressure, it's conceivable that the same gene variation may have opposing effects on blood pressure depending on genetic and environmental factors. Independent sets of data addressed in this study (acute BP response to saline infusion, incidence of hypertension in a 9-year follow-up population, age-related changes in BP) point to a favorable answer to this issue. As a result, the effect of a particular genetic variation on blood pressure must be assessed in the context of the relevant genetic epistatic interactions. In a group of individuals with the right genetic and environmental circumstances, a negative result or a small genetic impact in the general population may become a large gene effect.