Our bodies and those of our animal research subjects are colonized by bacterial communities that occupy virtually every organ system, including many previously considered sterile. These bacteria reside as complex communities that are collectively referred to as microbiota. Prior to the turn of the century, characterization of these communities was limited by a reliance on culture of organisms on a battery of selective media. It was recognized that the vast majority of microbes, especially those occupying unique niches of the body such as the anaerobic environment of the intestinal tract, were uncultivatable. However, with the onset and advancement of next-generation sequencing technology, we are now capable of characterizing these complex communities without the need to cultivate, and this has resulted in an explosion of information and new challenges in interpreting data generated about, and in the context of, these complex communities. We have long known that these microbial communities often exist in an intricate balance that, if disrupted (ie, dysbiosis), can lead to disease or increased susceptibility to disease. Because of many functional redundancies, the makeup of these colonies can vary dramatically within healthy individuals [1]. However, there is growing evidence that subtle differences can alter the phenotype of various animal models, which may translate to the varying susceptibility to disease seen in the human population. In this manuscript, we discuss how to include complex microbiota as a consideration in experimental design and model reproducibility and how to exploit the extensive variation that exists in contemporary rodent research colonies. Our focus will be the intestinal or gut microbiota (GM), but it should be recognized that microbial communities exist in many other body compartments and these too likely influence health and disease [2, 3]. Much like host genetics, can we one day harness the vast genetic capacity of the microbes we live with in ways that will benefit human and animal health?