The nonpathogenic, mutualistic bacteria of the mammalian gastrointestinal tract provide a number of benefits to the host. Recent reports have shown how the aggregate genomes of gastrointestinal bacteria provide novel benefits by functioning as the third major genome in mammals along with the nuclear and mitochondrial genomes. Consequently, efforts are underway to elucidate the complexity of the organisms comprising the unique ecosystem of the gastrointestinal tract, as well as those associated with other epidermal surfaces. The current knowledge of the gastrointestinal microbiome, its relationship to human health and disease with a particular focus on mammalian physiology, and efforts to alter its composition as a novel therapeutic approach are reviewed.