Background-Norepinephrine (NE) is a primary neurotransmitter of central autonomic regulation and sympathetic nerve conduction, and the norepinephrine transporter (NET) is crucial in limiting catecholaminergic signaling. NET is sensitive to antidepressants, cocaine, and amphetamine. NET blockade often is associated with cardiovascular side effects, and NET deficiency is linked to tachycardia in familial orthostatic intolerance. Methods and Results-We telemetrically monitored NET-deficient (NET Ϫ/Ϫ ) mice to determine the cardiovascular effects of reduced NE reuptake. Mean arterial pressure was elevated in resting NET Ϫ/Ϫ mice compared with NET ϩ/ϩ controls (103Ϯ0.6 versus 99Ϯ0.4 mm Hg; PϽ0.01), and corresponding pressures increased to 122Ϯ0.3 and 116Ϯ0.3 mm Hg (PϽ0.0001) with activity. Heart rate was also greater in resting NET Ϫ/Ϫ mice (565Ϯ5 versus 551Ϯ3 bpm; PϽ0.05), and genotypic differences were highly significant during the active phase (640Ϯ5 versus 607Ϯ3 bpm; PϽ0.0001). Conversely, the respiratory rate of resting NET Ϫ/Ϫ mice was dramatically reduced, whereas increases after the day/night shift surpassed those of controls. Plasma catecholamines in NET Ϫ/Ϫ and NET ϩ/ϩ mice were as follows: NE, 69Ϯ8 and 32Ϯ7; dihydroxyphenylglycol, 2ϩ0.4 and 17Ϯ3; epinephrine, 15Ϯ3 and 4Ϯ0.6; and dopamine, 13Ϯ4 and 4Ϯ1 pmol/mL. Catechols in urine, brain, and heart also were determined. Conclusions-Resting mean arterial pressure and heart rate are maintained at nearly normal levels in NET-deficient mice, most likely as a result of increased central sympathoinhibition. However, sympathetic activation with wakefulness and activity apparently overwhelms central modulation, amplifying peripheral catecholaminergic signaling, particularly in the heart.