Abstract The nervous system controls a variety of physiological responses through the release of several chemical messengers. Although the immune system has been thought to be a self-regulated system, there is growing evidence that the immune system and the nervous system are capable of reciprocally regulating their function. We recently identified a unique role for adrenergic signaling in modulating the innate response to pathogen-associated molecular patterns. First, we found that norepinephrine (NE) can suppress pro-inflammatory cytokine secretion from bone marrow-derived macrophages and dendritic cells in response to TLR signaling in vitro. This suppressive effect depends on the early induction of the anti-inflammatory cytokine IL-10, where neutralizing the autocrine IL-10 signaling restores the cytokine secretion. NE exerts its effects by signaling through the beta2-adrenergic receptor (ADRB2). Second, upon challenging mice with a sub-lethal dose of Listeria monocytogenes, ADRB2 knockout mice present with splenomegaly and enhanced bacterial clearance. Additionally, treatment of whole human blood with TLR ligands in the presence of the ADRB2 agonist albuterol suppresses TNFα secretion, demonstrating the presence of this pathway in humans. This supports the hypothesis that ADRB2 signaling is a negative regulator of TLR signaling and suggests that this pathway plays an important role in immune activation and homeostasis.