Plasma norepinephrine levels, which reflect sympathetic nervous system activity, are almost universally elevated in patients with left ventricular dysfunction. This elevation occurs in patients with overt, symptomatic heart failure (HF) and in patients with asymptomatic left ventricular dysfunction. Evidence suggests that the elevation in plasma norepinephrine levels can be at least partly attributed to an increase in sympathetic nervous system activity. It has become evident that elevated plasma norepinephrine levels are directly related to prognosis; patients with levels > 900 pg/ml have a poor prognosis and shortened life expectancy. However, plasma norepinephrine levels bear little relationship to physiologic and clinical variables observed in HF, including ejection fraction and exercise capacity. Data from the V-HeFT II show that at 2-year follow-up, a progressive rise of plasma norepinephrine was observed in both treatment arms, suggesting that disease progresses despite treatment with either an angiotensin-converting enzyme inhibitor, enalapril, or vasodilator therapy with hydralazine/isosorbide dinitrate. It is possible that interventions aimed at the progressive neurohormonal activation that occurs in HF may improve the course of illness. Further study is needed to test this hypothesis.