The gastrointestinal (GI) tract is essential for the absorption of nutrients, induction of mucosal and systemic immune responses and maintenance of a healthy gut microbiota. Key aspects of gastrointestinal physiology are controlled by the enteric nervous system (ENS), which is composed of enteric neurons and glial cells. The ENS is exposed to and interacts with the ‘outer’ (microbiota, metabolites and nutrients) and ‘inner’ (immune cells and stromal cells) microenvironment of the gut. Although the cellular blueprint of the ENS is mostly in place by birth, the functional maturation of intestinal neural networks is completed within the microenvironment of the postnatal gut, under the influence of gut microbiota and the mucosal immune system.