Host defense is a vital role played by the gastrointestinal tract. As host to an enormous and diverse microbiome, the gut has evolved an elaborate array of chemical and physicals barriers that allow the digestion and absorption of nutrients without compromising the mammalian host. The control of such barrier functions requires the integration of neural, humoral, paracrine and immune signaling, involving redundant and overlapping mechanisms to ensure, under most circumstances, the integrity of the gastrointestinal epithelial barrier. Here we focus on selected recent developments in the autonomic neural control of host defense functions used in the protection of the gut from luminal agents, and discuss how the microbiota may potentially play a role in enteric neurotransmission. Key recent findings include: the important role played by subepithelial enteric glia in modulating intestinal barrier function, identification of stress-induced mechanisms evoking barrier breakdown, neural regulation of epithelial cell proliferation, the role of afferent and efferent vagal pathways in regulating barrier function, direct evidence for bacterial communication to the enteric nervous system, and microbial sources of enteric neurotransmitters. We discuss these new and interesting developments in our understanding of the role of the autonomic nervous system in gastrointestinal host defense.