The intestine is described as an immune privileged site where immunoregulatory mechanisms simultaneously defend against pathogens, yet preserve tissue homeostasis to avoid immune-mediated pathology in response to environmental challenges. Additionally, tolerance to ingested antigens promotes the development of systemic unresponsiveness towards the same antigens. It is increasingly clear that this tolerance is a complex process that derives from the coordinated action of both canonical immune and non-immune cells at mucosal sites, including dendritic cells, macrophages and epithelial cells. Recent evidence suggests that dysregulation in gut-induced tolerance and commensal bacterial handling affects both local and systemic compartments and contributes to autoimmune disease. Understanding how tolerance is achieved at mucosal sites may thus be exploited to re-establish tissue homeostasis.