Approximately one-third of individuals over the age of 20 in developed countries have hypertension, and high blood pressure is recognized to be a major risk factor for coronary heart disease and stroke. The causes of the onset and the progressive increase in blood pressure over the course of a lifetime to eventually become diagnosed as frank hypertension are not known. Recently it has become more apparent that although heredity is a factor, the sum of the contributions of the identified genes affecting blood pressure cannot account for the incidence of hypertension. This is consistent with what has been described as the “missing heritability” of other complex diseases and has led others to propose that hypertension results from epigenetic mechanisms involving the interaction of genes X environment.In recent studies we developed an experimental approach in rats to explore the effects of antecedent physiological and psychological challenges (stressors) on the hypertensive response elicited by a subsequent treatment following an imposed intervening period of delay. This procedure is referred to as the INDUCTION-DELAY-EXPRESSION paradigm. Using this experimental design we have found that initial challenges with low, non-pressor doses of either angiotensin II or aldosterone given during INDUCTION significantly amplified the hypertensive response seen in a low-dose-angiotensin II-slow pressor model of hypertension which was given during EXPRESSION (i.e., test phase). The same antecedent treatments with either angiotensin II or aldosterone also enhanced salt sensitive hypertension which was demonstrated by giving access to 2% NaCl as the sole drinking fluid after the DELAY period.The enhancements in experimentally-induced hypertension as a result of exposure to subsequent stimuli are examples of response sensitization. Functional studies indicate that the sensitized hypertensive response is mediated by the central nervous system (CNS) and that the heightened responses are associated with sustained molecular changes in the central regions involved in blood pressure regulation. We have found that mRNA or protein of several biochemical factors which serve as putative markers of neuroplasticity (e.g., brain-derived neurotrophic factor, cAMP response element-binding protein) are increased in structures lying along the lamina terminalis, which comprise a forebrain region that is part of the neural network that controls blood pressure. Importantly in addition to these indices that are generally associated with memorial processes, there are sustained changes in this region of components of the brain-renin-aldosterone system.Taken together these findings indicate that stressors present at an earlier time can produce enduring changes in the CNS and suggest that these molecular changes result in increased responding to subsequent hypertension-eliciting challenges. Because of the observations of increased activity in the brain renin-angiotensin-aldosterone system in our sensitization studies, discussion will focus on the role of early activation of the systemic renin-angiotensin-aldosterone system and its influence on the central system as key mediators of stressors that have long-term influences on the regulation of blood pressure and pathogenesis of hypertension.