Sixty years ago, the American medical community was fairly ambivalent regarding hypertension, partly because there were few, if any, effective therapies, and partly because many physicians believed high blood pressure (BP) was an important compensatory response to reduced perfusion of the vital organs, and thus should not be treated.1 Although medicine has since made tremendous progress in the understanding and management of hypertension, the control of elevated BP in the general hypertensive population remains poor, with only an approximate one third of hypertensive patients achieving recommended BP goals.2 The pathogenesis of hypertension, its role in cardiovascular (CV) disease (CVD), and its optimal treatment still remain elusive.1 Recent findings from large epidemiologic studies indicate that the risks of CVD may begin to increase at BP levels well below 140/90 mm Hg, the current threshold for the definition and diagnosis of hypertension.3 Increasing evidence has also suggested that hypertension rarely occurs in isolation, but is usually associated with multiple CVD risk factors, such as dyslipidemia and hyperglycemia, which not only precipitate CVD but continuously contribute to its progression.4 These findings suggest that hypertension is not a mere function of a discrete BP level, but should be understood as part of a complex syndrome of pathologic changes in the vasculature and target organs, which may share common underlying pathogenic mechanisms.5 In line with this thinking, a new, more expansive definition of hypertension has been proposed by the Hypertension Writing Group.5 In addition, an increased emphasis has been placed in hypertension management on global CV risk reduction, including more sophisticated risk assessment and therapeutic targeting of underlying mechanisms of CVD, such as endothelial dysfunction and its hallmark characteristic, impaired nitric oxide (NO) bioactivity. This supplement is based on the symposium “Global Cardiovascular Risk Reduction: New Concepts and Therapeutic Opportunities,” offered at the 21st Annual Scientific Meeting and Exposition of the American Society of Hypertension, Inc., held in May 2006. The purpose of this supplement is to present recent perspectives on the role of hypertension as a component of a complex CVD syndrome, on endothelial dysfunction as a major pathogenic mechanism of this syndrome, and on potential therapeutic strategies based on these concepts for global CV risk reduction. This supplement should help update physicians on the newest and most useful concepts of hypertension, and on the progress toward optimal CV risk assessment and reduction. In the first article, I discuss some of the sobering epidemiologic trends showing that hypertension is far from being diminished as a public health problem, but is, in fact, expanding rapidly in prevalence worldwide.6,7 In this context, I discuss the evidence demonstrating the efficacy of BP lowering in reducing CVD risks and the current need for improved antihypertensive treatment. I also review the ever-expanding list of CVD risk factors and the efforts to improve global risk assessment, including a proposed redefinition of hypertension intended to support these efforts. The notable findings of the Trial of Preventing Hypertension (TROPHY) study8 are discussed to show how CVD global risk assessment should not rely solely on discrete BP levels and how early identification of high-risk patients and use of antihypertensive therapy can prevent hypertension. In the second article, Marvin Moser, MD provides a historical perspective which helps us see the general trends of hypertension research and treatment over the past 60 years and perhaps its future directions.1 Starting with the 1940s, Dr. Moser reviews the classic case of hypertensive heart disease suffered by President Franklin Delano Roosevelt, which illustrates the deadly consequences of untreated malignant hypertension and the dearth of effective therapies available at that time. Dr. Moser then traces the steady advances in the understanding and treatment of hypertension, with such landmarks as the development of thiazide diuretics and β blockers, and the establishment of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, and its issuance of regular reports and treatment guidelines. In concluding, Dr. Moser notes that the long-term trend of hypertension research and treatment has been toward earlier detection and aggressive treatment, with an emphasis on prevention; yet questions as to the precise nature of hypertension and the optimal modes of treatment and risk assessment still challenge investigators. Following Dr. Moser's article, Jan Basile, MD discusses the integrated and interactive mechanisms of CV risk factors and how they cumulatively contribute to the progression of CVD, with a focus on the role of hypertension.9 Dr. Basile also reviews recent research and recommendations on hypertension management, including the renewed emphasis on use of thiazide diuretics and questions raised about the role of β blockers.10,11 Analyzing the latter issue, Dr. Basile points out that recent data suggesting that β blockers are less effective in preventing stroke than other types of antihypertensive drugs are primarily based on use of the specific agent atenolol, which may not accurately represent the highly heterogeneous β-blocker class.11,12 To illustrate this point, Dr. Basile discusses the novel pharmacologic properties of the β blocker nebivolol, which induces endothelium-dependent vasodilation through activation of NO bioactivity, as contrasted with conventional, nonvasodilating β blockers such as atenolol.13 Dr. Basile also reviews the findings of the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS), which extend the clinical benefits of β blockade in the treatment of heart failure to a patient population more representative of the heart failure population present in the general community.14 Finally, R. Preston Mason, PhD reviews the latest perspectives and research findings on the role of impaired NO bioactivity in the pathogenesis of global CV risk.15 Citing recent data from studies conducted with nanotechnology, Dr. Mason describes the mechanisms of endothelial dysfunction at the cellular level and within the vessel wall, with a particular focus on the role of oxidative stress in atherogenesis. Dr. Mason then reviews the therapeutic effects of various pharmacologic agents on NO synthesis, including angiotensin-converting enzyme inhibitors, calcium channel blockers, statins, and the vasodilating β blocker nebivolol. Sharing nanotechnology findings, Dr. Mason elucidates the signal transduction pathway of nebivolol and reviews data showing the effects of nebivolol on NO release.16 These four articles should provide a balanced and highly up-to-date view of the exciting progress being made in hypertension management and the challenges that remain. In particular, they feature discussion of evolving theories on the nature of hypertension and global CV risk, and of the most advanced research on the mechanisms of NO bioactivity. A reading of this supplement should help prepare physicians to understand future advances in hypertension management and new research on pharmacologic targeting of NO bioactivity.