The ample expression of chemokines and their receptors by neurons in the brain suggests that they play a functional role beyond the coordination of inflammatory and immune responses. Growing evidence implicates brain chemokines in the regulation of neuronal activity and neurohormonal release. This study examined the potential role of brain chemokines in regulating hemodynamic, sympathetic, and neuroendocrine mechanisms in rats with ischemia-induced heart failure (HF). Immunohistochemical analysis revealed that the chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12 was highly expressed in the hypothalamic paraventricular nucleus and subfornical organ and that SDF-1 expression was significantly increased in HF rats compared with sham-operated (SHAM) control rats. ICV injection of SDF-1 induced substantial and long-lasting increases in blood pressure, heart rate, and renal sympathetic nerve activity in both SHAM and HF rats, but responses were exaggerated in HF rats. Bilateral microinjection of SDF-1 into the paraventricular nucleus also elicited exaggerated increases in blood pressure, heart rate, and renal sympathetic nerve activity in the HF rats. A 4-hour ICV infusion of SDF-1 increased plasma levels of arginine vasopressin, adrenocorticotropic hormone, and norepinephrine in normal rats, responses that were prevented by pretreatment with ICV SDF-1 short-hairpin RNA (shRNA). ICV administration of SDF-1 shRNA also reduced plasma arginine vasopressin, adrenocorticotropic hormone, and norepinephrine levels in HF rats. These data suggest that the chemokine SDF-1, acting within the brain, plays an important role in regulating sympathetic drive, neuroendocrine release, and hemodynamic function in normal and pathophysiological conditions and so may contribute to the neural and humoral activation in HF.