The structural upward resetting of heart, vessels, and barostat functions represents what may be the most important long-term cardiovascular alteration in hypertension; the altered geometric design of the systemic precapillary resistance vessels is of profound hemodynamic relevance. This is especially true in primary (essential) hypertension, for which three major etiological elements can be distinguished: poly-genetic predisposition, environmental factors, and the structural factor. The physical and biological principles behind the early “structural upward resetting” of heart and vessels in hypertension are outlined and experimentally illustrated. Further, the long-term hemodynamic effects of this per se “normal” structural adaptation are discussed, particularly concerning systemic precapillary resistance, but also concerning the heart, barostat mechanisms of reflex and renal nature, and the venous capacitance vessels. With this background in mind, the primary long-term goal of therapy must be to reverse these structural changes toward normal cardiovascular design and dimensions, whereas in the future preventive measures may be actualized. Thus, treatment should serve not only to reduce the increased load on heart and vessels but also, wherever possible, to reduce the influence of trophic, growth-promoting factors of local and remote nature, as exemplified by model studies in rats.