Trillions of commensal microbes reside on and inside the human body, including the intestinal and respiratory tracts, which encompass various microbial taxa, such as bacteria, fungi, archea and viruses. The close proximity of microbes with the host provides an opportunity to continually interact with each other. Advances in research approaches, including high-throughput sequencing, have allowed us to study host and commensal microbes at the genetic and functional levels. Recent studies suggest that commensal microbes play a crucial role in the development of the host’s immune system and induce innate and adaptive immune responses against pathogens. It is also becoming apparent that the gut commensals are endowed with a capacity to alter immune responses in organs beyond the intestine, such as the lungs, highlighting the significance of the gut commensals in controlling systemic immunity. On the other hand, the host’s immune system possesses the ability to shape the repertoire of commensal microbes and contribute to the establishment of beneficial relationships with them. A better understanding of host-commensal interactions will be important for designing effective vaccines and therapeutics against pathogens. This Research Topic sheds light on our current understanding of the interplay between the host’s immune system and commensal microbes and how this interplay can be exploited for prophylactic and/or therapeutic strategies against pathogens.