The current challenge facing clinicians is to develop pharmacotherapies that move beyond the treatment of symptoms towards a new agenda in cardiovascular therapeutics that includes interventions to actually prevent the development of end-stage coronary heart disease. The development of new strategies to alter the natural history of cardiovascular disease will be fostered by gaining insights into the fundamental pathobiological mechanisms that promote the morbidity and mortality associated with these disorders. An emerging body of evidence indicates that locally generated vasoactive substances such as angiotensin II and nitric oxide are important determinants of the natural history of vascular disease. It is anticipated that ongoing clinical trials will extend the concept that modulating the activity of vasoactive substances generated by the endothelium has important implications for altering the course of coronary heart disease.