Physiologic anti-inflammatory mechanisms are selected by evolution to control the immune system and to prevent infectious and inflammatory disorders. Central-acting alpha2-agonists attenuate systemic inflammation and improve survival in experimental sepsis. This anti-inflammatory and therapeutic mechanism of central sympatholytics appears to be mediated by an unexpected vagomimetic potential of the alpha2-agonists to activate the vagus nerve. Recent studies, however, rule out a cholinergic anti-inflammatory mechanism based on a direct cholinergic interaction between the vagus nerve and the immune system. Since the nervous system is the principal regulator of the immune system, physiologic studies understanding the neuroimmune connections can provide major advantages to design novel therapeutic strategies for sepsis.