The microbiota is an important factor in the development of the immune response. The interaction between the gastrointestinal tract and resident microbiota is well balanced in healthy individuals, but its breakdown can lead to intestinal and extraintestinal disease. We review current knowledge about the mechanisms that regulate the interaction between the immune system and the microbiota, focusing on the role of resident intestinal bacteria in the development of immune responses. We also discuss mechanisms that prevent immune responses against resident bacteria, and how the indigenous bacteria stimulate the immune system to protect against commensal pathobionts and exogenous pathogens. Unraveling the complex interactions between resident intestinal bacteria and the immune system could improve our understanding of disease pathogenesis and lead to new therapeutic approaches.