A successful host response to infection requires extensive coordination of distinct immune defenses to maximize pathogen clearance while minimizing immunopathology. While we have gained a significant understanding of some of the critical regulators of innate and adaptive defenses, very little is known about immune-regulation by one of the most important regulators of all organ systems, the nervous system. Apart from regulating physiological responses to infection, the nervous system has recently been shown to suppress inflammation and regulate both macrophage and T cell responses in the spleen. We have demonstrated that sensory neurons regulate innate immune responses to Gram-negative bacterial pathogens in the model organism Caenorhabditis elegans. G protein coupled receptor (GPCR) signaling in specific subsets of sensory neurons modulates immunity via unfolded protein response (UPR) and p38 mitogen activated protein kinase (MAPK) pathways. Stress response pathways in the endoplasmic reticulum and in the cytosol regulate innate immune defenses. Further, we can utilize C. elegans, as a genetically tractable host, to understand how microbial infection activates neural GPCR signaling, which results in innate immune regulation of infection and pathogen clearance. Architecture of the nervous system, GPCR signaling, and neurotransmitter signaling is conserved across animal taxa. Thus, studies in C. elegans are likely to pave the way for novel anti-microbial immune-modulatory therapeutics, utilizing drugs that target GPCR or neurotransmitter signaling in the human nervous system.