The vasculature is an integrated organ capable of modulating its structure in accordance with hemodynamic conditions and locally generated mediators. Vasoactive substances produced within the vasculature are important modulators of vessel structure and vessel tone. This review focuses on the pathogenic role of vasoactive substances in vascular remodeling in hypertension and the potential clinical implications of this pathobiological process. It is speculated that therapeutic strategies that influence vascular remodeling may be clinically more effective.