Sympathetic neural overactivity is a major contributor to the progressive decline in cardio-renal function that occurs in chronic heart failure (CHF). In addition, breathing dysregulation is often associated with CHF, which in turn likely aggravates the autonomic imbalance. Maladaptive tonic activation of the carotid body (CB) chemoreflex contributes to this sympathetic over activity and breathing instability. CB ablation reduces chronic sympathetic outflow and improves breathing stability, renal and cardiac function, and survival in CHF animals, confirming a dysregulatory role of the CB in CHF. The tonic increase in CB afferent activity and chemoreflex drive that contributes to its maladaptive role in CHF is likely driven by a number of neuro-humoral and hemodynamic factors that are altered in CHF. There is a marked change in redox state in the CB of CHF animals (rats, rabbits) toward elevated reactive oxygen species (ROS) production. This is mediated, in part, by an upregulation of NOX2 superoxide production driven by increased angiotensin II and other possible factors also know to be elevated in CHF such as endothelin-1 and inflammatory cytokines. The elevated oxidative burden is further aggravated by downregulation of antioxidant systems such as SOD1 and SOD2 in the CB. The increased ROS inhibits hyperpolarizing K+ channels in CB glomus cells to enhance afferent excitability. Conversely, nitric oxide (NO) plays an important role in tempering CB glomus cells excitability by facilitating activation of voltage gated K+ channels, NO production in the CB is markedly suppressed in CHF due to downregulation of both nNOS and eNOS in CB cells. These changes appear to be driven by a chronic reduction in blood flow to the CB. A chronic reduction in blood flow to the CB, resembling that seen in CHF, recapitulates the molecular and functional changes in the CB that occur in CHF animals. To explore the molecular mechanisms responsible for these effects, we assessed the role of a flow-mediated transcription factor Krüppel-like Factor 2 (KLF2) in the CB of CHF animals. KLF2 plays an important role in the suppression of angiotensin converting enzyme and activation of nitric oxide synthase expression, and KLF2 is downregulated in the CB of CHF animals. Adenoviral transfection of KLF2 to the CB in CHF rabbits markedly reduces resting renal sympathetic nerve activity (RSNA) and CB chemoreflex sensitivity, and normalizes breathing stability and autonomic indices. In addition KLF2 knockdown (siRNA) in the CB of normal rabbits increases CB chemoreflex sensitivity, resting RSNA, heart rate, oscillatory breathing, cardiac autonomic imbalance, and arrhythmia incidence, similar to the sequelae of events that occur in CHF. The translational implications of these studies are discussed in relation to potential therapies for CHF.