Hypertension is one of the most common complex disorders that continues to affect millions people around world. Hypothalamic orexin participates in the regulation of breathing, sympathetic nerve activity (SNA) and blood pressure, and has recently been linked with neurogenic hypertension. Using SHRs at two ages, P30-58 and adult (4-8month), we (Li et al, 2013 & 2016) recorded breathing (whole-body plethysmograph) and arterial blood pressure (ABP; radio-telemetry) in wakefulness and sleep, and showed that 1) An augmented CO2 chemoreflex and higher ABP are measureable at a young age (P30-58) and increase in adulthood. In wakefulness, for example, the ventilatory response to normoxic-hypercapnia is higher in young SHRs (179±11SEM %increase) than in age-matched normotensive Wistar-Kyoto (WKY) rats (114±9% increase), but lower than in adult SHRs (226±10% increase) (P<0.05). The resting ABP is higher in young SHRs (122±5 mmHg) than in age-matched WKY rats (99±5 mmHg), but lower than in adult SHRs (152± 4mmHg) (P<0.05). 2) Antagonism of orexin receptors with a dual orexin receptor antagonist, almorexant (oral 200mg/kg, or subcutaneous 32mg/kg), can a) normalize the augmented CO2 chemoreflex in young and adult SHRs and the high ABP in young SHRs, and significantly lower ABP in adult SHRs; b) significantly decrease sympathetic vasomotor tone and noradrenaline levels in cerebrospinal fluid and plasma. 3) Attenuation of peripheral chemoreflexes by hyperoxia does not abolish the augmented CO2 chemoreflex in SHRs, which indicates an important role for the central chemoreflex. 4) SHRs have more orexin neurons in the hypothalamus than normotensive WKY rats at both young and adult ages, and moreover, hypercapnia activates more orexin neurons (marked by c-fos) in the hypothalamus in SHRs than in age-matched normotensive WKY rats. We speculate that in SHRs the upregulated orexin system produces long-term excitatory drive to many cardiorespiratory related nuclei in the brainstem and spinal cord projection sites and results in a long-term increase in the CO2 chemoreflex, SNA and ABP. The sustained increased SNA may induce partially irreversible changes in vascular smooth muscle of resistance vessels. Down regulating the orexin system, e.g., blocking orexin receptors, can, at least partially, remove the elevated orexin-excitatory input on these cardiovascular nuclei and vascular smooth muscle cells resulting in a depressor effect, lowering SNA, ABP and CO2 chemoreflex. In conclusion an overactive orexin system may play a significant role in the development and maintenance of high ABP and enhanced CO2 chemoreflex in neurogenic hypertension in SHRs. Modulation of the overactive orexin system and CO2 chemoreflex could be a potential target in treating neurogenic hypertension.