The chapter discusses the intricate interactions between the microbiota and the immune system, highlighting their mutualistic nature and the challenges posed by the coexistence of these two systems. The mammalian immune system plays a crucial role in maintaining homeostasis with resident microbial communities, ensuring the stability of the host-microbial relationship. At the same time, resident bacteria significantly influence mammalian immunity. The chapter reviews advances in understanding these interactions, emphasizing the importance of tools like gnotobiotic animals and high-throughput sequencing technologies in advancing research. It also explores how the immune system controls the localization and composition of the microbiota, and how the microbiota shapes host immunity, including the development of lymphoid structures and the regulation of T cell subsets. The chapter concludes by outlining future challenges and perspectives, emphasizing the need for further research to deepen our understanding of these complex interactions and their implications for human health.The chapter discusses the intricate interactions between the microbiota and the immune system, highlighting their mutualistic nature and the challenges posed by the coexistence of these two systems. The mammalian immune system plays a crucial role in maintaining homeostasis with resident microbial communities, ensuring the stability of the host-microbial relationship. At the same time, resident bacteria significantly influence mammalian immunity. The chapter reviews advances in understanding these interactions, emphasizing the importance of tools like gnotobiotic animals and high-throughput sequencing technologies in advancing research. It also explores how the immune system controls the localization and composition of the microbiota, and how the microbiota shapes host immunity, including the development of lymphoid structures and the regulation of T cell subsets. The chapter concludes by outlining future challenges and perspectives, emphasizing the need for further research to deepen our understanding of these complex interactions and their implications for human health.