It is well established that the sympathetic nervous system plays a vital role in the regulation of physiological homeostasis. However, accumulating evidence suggests that sympathetic nerve activity (SNA) becomes excessively heightened in many disease states. Importantly, elevations in SNA have been associated with impairments in cardiac, vascular, metabolic and renal function (Fisher et al., 2009), and poor survival in patients with end-stage renal disease and chronic heart failure (Converse et al., 1992; Barretto et al., 2008). Although, the adverse consequences of sympathetic over-activity may in part be attributable to its potential role in the development of hypertension, it is notable that the deleterious effects of elevations in SNA may also occur independently of elevations in blood pressure (Fisher et al., 2009). As such, therapeutic strategies targeting reductions in sympathetic over-activity are clinically desirable (Grassi, 2004), and thus identification of the mechanisms underlying this neural dysfunction is important. The pathological alterations that occur in the central regulation of SNA are highly complex and have been suggested to involve numerous autonomic reflexes, central neuroanatomical sites, neurotransmitters and local factors (e.g. angiotensin II, reactive oxygen species, nitric oxide, and inflammatory cytokines). Indeed, recent work from both animal and human studies has highlighted the contribution of centrally derived nitric oxide in the genesis of sympathetic over-activity (Zucker, 2006; Young et al., 2008). However, recent novel interventions, including exercise training and pharmacological administration (e.g. statins, rilmenidine) have shown promise in attenuating ‘central’ sympathetic over-activity in animals and limited human studies (Zucker, 2006; Fisher et al., 2007; Fisher et al., 2009). Further work is critical to more fully elucidate the mechanisms underlying pathological elevations in sympathetic outflow, and to develop effective therapeutic strategies to counteract this neural dysfunction in patient populations.