Abnormal neurohumoral activation (as seen in hypertension) is a negative prognostic indicator for sudden cardiac death and a strong independent predictor of mortality. Our work and that of others has recently established that nitric oxide (NO) inhibits cardiac sympathetic activity, decreases adrenergic regulation of ICaL in sino atrial node cells, and facilitates cardiac parasympathetic transmission. This talk will review the emerging evidence that supports the idea that upregulation of neuronal NOS by either exercise training or gene transfer is beneficial in restoring the normal cardiac neural phenoptype. However, a reduction in NO bioavailability in hypertension caused by oxidative stress impairs cyclic nucleotide signalling and contributes to sympathetic hyper-responsiveness and vagal impairment. Overexpression of nNOS into cardiac sympathetic nerves induced by cell specific adenoviral gene transfer can rescue this effect by increasing cGMP dependent modulation of intracellular calcium leading to normal neurotransmission. The significance of these observations in the wider context of cardiac neural control will be discussed.