The microbiota plays a fundamental role on the induction, training and function of the host immune system. In return, the immune system has largely evolved as a means to maintain the symbiotic relationship of the host with these highly diverse and evolving microbes. When operating optimally this immune system–microbiota alliance allows the induction of protective responses to pathogens and the maintenance of regulatory pathways involved in the maintenance of tolerance to innocuous antigens. We will discuss how in the skin and the GI tract alliance between microbes and tissue immune networks control both immunity and pathogenesis to infection and the long-term consequences these interactions for host homeostasis.