AIMS: The corticotrophin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus critically regulate neuroendocrine and autonomic nervous system function. Primary hypertension patients display an increase in hypothalamic CRH levels. However, the role of PVN-CRH neurons in the pathogenesis of primary hypertension remains unclear. METHODS AND RESULTS: Here, we showed that the PVN-CRH neurons were juxtaposed to neurons projecting to the rostral ventrolateral medulla (RVLM), a brain stem region crucial for regulating cardiovascular functions. Optical stimulation of PVN-CRH neurons with selective expression of light-sensitive channel channelrhodopsin-2 (ChR2) on these neurons increased blood pressure (BP) in conscious Wistar-Kyoto (WKY) rats and the activity of PVN-RVLM neurons, an effect abolished by blocking CRHRs with astressin. Optical stimulation of PVN-CRH neurons also significantly increased plasma levels of norepinephrine (NE) and copeptin, a stable surrogate marker for vasopressin. Compared to WKY rats, PVN-CRH neurons in spontaneously hypertensive rats (SHRs) display a significantly high firing activity, increased glutamatergic synaptic inputs and NMDA receptor activity. Optical inhibition of PVN-CRH neurons by expressing inhibitory light-sensitive channel stGtACR2 s on these neurons decreased BP in SHRs and suppressed PVN-RVLM neurons. The plasma NE and adrenocorticotropic hormone (ACTH) levels were significantly lower after inhibiting PVN-CRH neurons. Furthermore, the ablation of PVN-CRH neurons by selective expression of Casp3 decreased BP in adult SHRs and suppressed hypertension development in young SHRs. CONCLUSION: These findings suggest that the PVN-CRH neurons play a pivotal role in the pathogenesis of hypertension through interacting with PVN-RVLM neurons and that the hyperactivity of PVN-CRH neurons contribute to high vasopressin levels and the onset and maintenance of primary hypertension.