Recent advances in understanding how the mammalian immune system and intestinal microbiota functionally interact have yielded novel insights for human health and disease. Modern technologies to quantitatively measure specific members and functional characteristics of the microbiota in the gastrointestinal tract, along with fundamental and emerging concepts in the field of immunology, have revealed numerous ways in which host-microbiota interactions proceed beneficially, neutrally, or detrimentally for mammalian hosts. It is clear that the gut microbiota has a strong influence on the shape and quality of the immune system; correspondingly, the immune system guides the composition and localization of the microbiota. In the following review, we examine the evidence that these interactions encompass homeostasis and inflammation in the intestine and, in certain cases, extraintestinal tissues. Lastly, we discuss translational therapies stemming from research on host-microbiota interactions that could be used for the treatment of chronic inflammatory diseases.