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Interactions between the nervous and immune systems enable the gut to respond to the variety of dietary products that it absorbs, the broad spectrum of pathogens that it encounters, and the diverse microbiome that it harbors. The enteric nervous system (ENS) senses and reacts to the dynamic ecosystem of the gastrointestinal (GI) tract by translating chemical cues from the environment into neuronal impulses that propagate throughout the gut and into other organs in the body, including the central nervous system (CNS). This review will describe the current understanding of the anatomy and physiology of the GI tract by focusing on the ENS and the mucosal immune system. We highlight emerging literature that the ENS is essential for important aspects of microbe-induced immune responses in the gut. Although most basic and applied research in neuroscience has focused on the brain, the proximity of the ENS to the immune system and its interface with the external environment suggest that novel paradigms for nervous system function await discovery.After its initial discoveries in the 1980s and 1990s, neuro-immunology is experiencing a rebirth in the scientific literature. As knowledge of the gastrointestinal tract expands, including its neuronal, immunological, and microbial constituents, in this review, Yoo and Mazmanian provide new perspectives and hypotheses regarding mucosal neuro-immunology.